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Indian Institute of Science Education and Research Pashan Pune India
daggerCentre for Biomolecular Interactions Bremen University of Bremen Bremen Germany
DaggerCentre for Environmental Research and Sustainable Technology Bremen Germany
Abstract
Formaldehyde is an environmental pollutant that is alsogenerated in substantial amounts in the human body during
normal metabolism This aldehyde is a well-established
neurotoxin that affects memory learning and behavior In
addition in several pathological conditions including Alzhei-
mer rsquos disease an increase in the expression of formaldehyde-
generating enzymes and elevated levels of formaldehyde in
brain have been reported This article gives an overview on
the current knowledge on the generation and metabolism of
formaldehyde in brain cells as well as on formaldehyde-
induced alterations in metabolic processes Brain cells have
the potential to generate and to dispose formaldehyde In
culture both astrocytes and neurons ef1047297ciently oxidize form-
aldehyde to formate which can be exported or further oxidized
Although moderate concentrations of formaldehyde are not
acutely toxic for brain cells exposure to formaldehydeseverely affects their metabolism as demonstrated by the
formaldehyde-induced acceleration of glycolytic 1047298ux and by
the rapid multidrug resistance protein 1-mediated export of
glutathione from both astrocytes and neurons These formal-
dehyde-induced alterations in the metabolism of brain cells
may contribute to the impaired cognitive performance
observed after formaldehyde exposure and to the neurode-
generation in diseases that are associated with increased
formaldehyde levels in brain
Keywords formaldehyde glutathione glycolysis metabolism
neurodegeneration neurotoxicity
J Neurochem (2013) 127 7ndash 21
Formaldehyde chemistry
Formaldehyde (HCHO) is the simplest aldehyde that is also
known as methanal This compound was 1047297rst described in
1855 by Alexander Butlerov while its chemical synthesis by
methanol dehydration was 1047297rst achieved in 1867 by August
Wilhelm von Hofmann (Salthammer et al 2010) In the
following decades the properties of formaldehyde were
extensively studied and this compound was one of the
earliest to obtain a CAS registry number (50-00-0) Form-
aldehyde is highly reactive It can undergo hydration and
forms hemiacetals with alcohols or thiohemiacetals with
thiols Formaldehyde also reacts with amines to form Schiff
bases and cross-links proteins by forming methylene bridges
between amino groups (Metz et al 2004 2006) This high
reactivity of formaldehyde is the reason for its extensive use
in industries (Tang et al 2009)
Due to its protein cross-linking ability formaldehyde is
frequently used for tissue preservation and 1047297xation (Nazar-
ian et al 2009) Formalin solution that is used in pathology
contains 35 formaldehyde while for 1047297xation of tissues
tissue sections or cultured cells a 4 formaldehyde
solution is frequently used (Kiernan 2000) Such a 4
formaldehyde solution contains the aldehyde in a concen-
tration of above 1 M Thus the concentrations of formal-
dehyde that are used for technical processes are several
orders of magnitude higher than the concentrations of
Received May 30 2013 revised manuscript received June 12 2013
accepted June 21 2013
Address correspondence and reprint requests to Dr Ralf Dringen
Centre for Biomolecular Interactions Bremen University of Bremen
PO Box 330440 D-28334 Bremen Germany
E-mail ralfdringenuni-bremende
Abbreviations used AD Alzheimer rsquos disease ADH alcohol dehy-
drogenase ALDH aldehyde dehydrogenase GSH glutathione GSSG
glutathione disul1047297de JHDM JmjC domain-containing histone demeth-
ylases LSD lysine-speci1047297c demethylase MCT monocarboxylate
transporter Mrp multidrug resistance protein MS multiple sclerosis
MTHFD methylene tetrahydrofolate dehydrogenase SSAO semicar-
bazide-sensitive amine oxidases THF tetrahydrofolate VAP vascular
adhesion protein
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JOURNAL OF NEUROCHEMISTRY | 2013 | 127 | 7ndash21 doi 101111jnc12356
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formaldehyde (01 ndash 04 mM) that are found in body 1047298uids
and tissues under normal and pathological conditions (Heck
and Casanova 2004 Tong et al 2013a)
Endogenous and exogenous sources of formaldehyde
Formaldehyde exposure is caused by the generation of this
aldehyde within the body and can also be a consequence of
contact with elevated levels of environmental formaldehyde
(Fig 1) Some of the endogenous enzymatic reactions that
generate formaldehyde as well as exogenous sources of
formaldehyde are described below
Formaldehyde is the oxidation product of methanol This
alcohol can be generated within the body by hydrolysis of
protein carboxymethyl esters either non-enzymatically or
catalyzed by methylesterases (Lee et al 2008) In addition
accidental or intentional intake of methanol will further
expose the body to this alcohol In cells methanol is oxidized
to formaldehyde by alcohol dehydrogenase (ADH) 1 by
catalase or by a non-enzymatic reaction of methanol with
hydroxyl radicals (Harris et al 2003 MacAllister et al
2011) In humans and primates ADH1 appears to be
predominately responsible for methanol oxidation while
the majority of methanol oxidation in rats has been reported
to be mediated by catalase (Tephly 1991 Skrzydlewska
2003)
Another endogenous source of formaldehyde are semicar-
bazide-sensitive amine oxidases (SSAO) which represent agroup of copper-containing amine oxidases that are inhibited
by semicarbazide and most of them contain topa-quinone at
their catalytic centre (Jalkanen and Salmi 2001 Yu et al
2003) Oxidative deamination of methylamine by SSAO
generates formaldehyde together with ammonia and hydro-
gen peroxide (Yu et al 2003 OrsquoSullivan et al 2004) In
mammals SSAO are either membrane-associated or circulate
in a soluble form in the vascular system (Jalkanen and Salmi
2001) Among the SSAO the vascular adhesion protein
(VAP) 1 is one of the most extensively studied members of
this group of enzymes (Smith and Vainio 2007 Jalkanen and
Salmi 2008)
Formaldehyde is also generated as by-product of reactions
catalyzed by lysine-speci1047297c demethylase (LSD) 1 and JmjC
domain-containing histone demethylases (JHDM) (Cloos
et al 2008 Hou and Yu 2010) These enzymes remove
methyl groups from lysine residues in histones thereby
altering the chromatin structure (Cheng and Zhang 2007
Cloos et al 2008 Hou and Yu 2010 Izzo and Schneider
2010) LSD1 is a 1047298avin-containing enzyme that selectively
demethylates the mono- or dimethylated lysine residue in
position 4 of histone H3 (Forneris et al 2009 Hou and Yu
2010) On the other hand JHDM can remove methyl groups
from mono- di- or trimethylated lysine residues and require
Fe2+
and a-ketoglutarate as cofactors (Cloos et al 2008 Houand Yu 2010)
In addition to endogenous sources the body can also
encounter environmental formaldehyde since a number of
commonly used products contain either formaldehyde or
formaldehyde-releasing substances (Sasseville 2004
de Groot et al 2009) Some examples of such products are
construction materials agricultural fertilizers fumigants
paints cosmetics antiperspirants polish cleaning agents
and toiletries (Sasseville 2004 de Groot et al 2009 2010)
In addition formaldehyde can be produced and released from
burning of wood coal tobacco natural gas and kerosene
(de Groot et al 2009 Laitinen et al 2010) Moreover foods
like coffee cod1047297sh meat poultry and maple syrup naturally
contain formaldehyde (Dhareshwar and Stella 2008 de
Groot et al 2009) Thus this ubiquitously present compound
can enter the human body by inhalation ingestion or entry
through the skin
One pertinent question is whether exogenous formalde-
hyde can pose a big threat to the central nervous system by
entering the blood and ultimately reaching the brain after
crossing the blood ndash brain barrier In healthy individuals the
formaldehyde concentration in the blood is around 01 mM
(Heck and Casanova 2004) and that in the brain is
02 ndash 04 mM (Tong et al 2013a) Inhalation of moderate
Fig 1 Endogenous and exogenous sources of formaldehyde (HCHO)
and pathways involved in cellular formaldehyde disposal For details
see text ADH alcohol dehydrogenase ALDH aldehyde dehydroge-
nase cy cytosolic JHDM JmjC domain-containing histone demeth-
ylases LSD lysine-speci1047297c demethylase mt mitochondrial MTHFD
methylene tetrahydrofolate dehydrogenase SSAO semicarbazide-
sensitive amine oxidases VAP vascular adhesion protein
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doses of formaldehyde does not severely increase the
formaldehyde level in blood (Heck et al 1985 Franks
2005) This is expected as the formaldehyde-oxidizing
enzymes ADH3 and aldehyde dehydrogenase (ALDH) 2
(Fig 1) are ubiquitously expressed in all tissues (Nishimuraand Naito 2006 Alnouti and Klaassen 2008) and will
quickly clear a low excess of environmentally derived
formaldehyde However exposure to high concentrations of
exogenous formaldehyde that exceeds the peripheral form-
aldehyde oxidation capacity will elevate the normal tolerable
concentration of formaldehyde in the blood and could lead
to neural damage Indeed exposure to exogenous formal-
dehyde has been reported to cause neurotoxicity in humans
and animals and the extent of damage depends on the dose
of formaldehyde and the duration of the exposure (Kilburn
et al 1985a b Songur et al 2008 2010) Especially
individuals who carry functional polymorphisms in the
genes encoding for formaldehyde-metabolizing enzymes
ADH3 or ALDH2 which are discussed to be associated with
reduced formaldehyde-oxidizing capacity (Hedberg et al
2001 Wang et al 2002) may be more vulnerable to
neural damage by endogenously generated or environmental
formaldehyde
Metabolism of formaldehyde
Despite of the multiple endogenous and exogenous sources
of formaldehyde a low physiological level of formaldehyde
in body 1047298uids and tissue is maintained by the continuous
action of cellular formaldehyde-metabolizing enzymes(Fig 1) ADH1 is considered to play a negligible role in
formaldehyde reduction to methanol because of its very high
KM-value for formaldehyde (about 30 mM) (Skrzydlewska
2003) The formaldehyde oxidation product formate is
generated by two independent pathways that are mediated
by either the mitochondrial ALDH2 or the cytosolic ADH3
(Teng et al 2001 Friedenson 2011 MacAllister et al
2011) ADH3 also known as glutathione (GSH)-dependent
formaldehyde dehydrogenase oxidizes formaldehyde to
formate in a two-step process (Harris et al 2003 Staab
et al 2009 Thompson et al 2010 MacAllister et al 2011)
In the 1047297rst step GSH reacts with formaldehyde in an
enzyme-independent manner to form S-hydroxymethyl GSH
that is subsequently used as ADH3 substrate to generate S-
formyl GSH (Harris et al 2003 Staab et al 2009 Thomp-
son et al 2010 MacAllister et al 2011) The conjugate S-
formyl GSH is hydrolyzed by a thiolase to generate formate
and GSH (Teng et al 2001 Harris et al 2003 MacAllister
et al 2011) Unlike ADH3 the reaction catalyzed by
ALDH2 is a single-step GSH-independent process (Teng
et al 2001 MacAllister et al 2011) Since ADH3 has a
very low KM-value for S-hydroxymethyl GSH (less than
10 lM) compared to that of ALDH2 for formaldehyde (02 ndash
05 mM) (Casanova-Schmitz et al 1984 Heck et al 1990)
ADH3 is likely to be especially important for the oxidation
of low concentrations of formaldehyde
The formate generated by formaldehyde oxidation can
undergo further oxidization to carbon dioxide in a metabolic
pathway involving tetrahydrofolate (THF) wherein formateis 1047297rst converted to 10-formyl THF (Fig 1) in an ATP-
dependent reaction (Skrzydlewska 2003 Krupenko 2009
Krupenko et al 2010) This reaction is catalyzed either by
the cytosolic methylene tetrahydrofolate dehydrogenase
(MTHFD) 1 or by its mitochondrial isoform MTHFD1L
(Tibbetts and Appling 2010) 10-formyl THF is subsequently
oxidized by the cytosolic 10-formyl THF dehydrogenase
also known as ALDH1L1 or its mitochondrial isoform
ALDH1L2 to carbon dioxide Both enzymes use NADP+ as a
co-factor and regenerate THF (Skrzydlewska 2003 Kru-
penko 2009 Krupenko et al 2010) Although formate
oxidation takes place predominantly by the THF-dependent
pathway catalase-mediated oxidation of formate has also
been reported (Cook et al 2001 Skrzydlewska 2003)
Formaldehyde metabolism (Fig 1) is best studied for the
liver (Skrzydlewska 2003 Tibbetts and Appling 2010) but it
is very likely that other organs including the brain will also
use the enzymatic pathways that are well known for
formaldehyde metabolism in liver In brain at least all the
enzymes required for complete formaldehyde oxidation are
expressed (Table 1)
Differences in the rate of formaldehyde metabolism have
been described between species for the formaldehyde
metabolism For example formate is metabolized at a slower
rate in the liver of monkeys and humans compared to ratspartly because rats have a higher hepatic THF content
(Tephly 1991 Skrzydlewska 2003) Also species-speci1047297c
differences in the kinetic parameters of the enzymes involved
in formaldehyde metabolism may contribute to the different
rates of formaldehyde oxidation observed and subsequently
may determine the consequences of an exposure to formal-
dehyde andor it metabolites
Generation and oxidation of formaldehydein brain cells
Several reports have demonstrated that the enzymes required
to produce or metabolize formaldehyde are expressed in the
brain on the mRNA or protein level (Table 1) Of these
enzymes only the expression of ADH1 in the brain has been
controversially discussed since this dehydrogenase was not
detected in brain by some investigators (Julia et al 1987
Galter et al 2003) Despite the presence of ADH1 mRNA in
cultured neural cells methanol generation was not found for
formaldehyde-exposed cultured brain cells (Tulpule and
Dringen 2012 Tulpule et al 2013) suggesting that oxida-
tion to formate is the preferred pathway of formaldehyde
metabolism in brain cells Cultured astrocytes and neurons
contain the mRNAs for SSAO and LSD1 as well as for the
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Formaldehyde in brain 9
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enzymes involved in formaldehyde metabolism (Tulpule and
Dringen 2012 Tulpule et al 2013) These studies indicate
that formaldehyde may be produced locally in the brain and
that among the different types of brain cells at least astrocytes
and neurons have the potential to generate and oxidize
formaldehyde
Acute formaldehyde exposure in concentrations of up to
1 mM for up to 3 h does not cause severe toxicity in cultured
astrocytes or neurons (Song et al 2010 Tulpule and Dringen2011 2012 Tulpule et al 2013) A rapid metabolism of
cellular formaldehyde may contribute to the resistance of
cultured brain cells to formaldehyde toxicity since formal-
dehyde has been reported to be more cytotoxic than its
metabolites methanol and formate (Oyama et al 2002 Lee
et al 2008) Both cultured astrocytes and neurons clear
exogenously applied formaldehyde with a similar rate of
around 02 lmol(h 9 mg) (Tulpule and Dringen 2012
Tulpule et al 2013) which is about 20 of the formaldehyde
oxidation rate reported for liver cells (Dicker and Cederbaum
1984) The K M-value for formaldehyde clearance by cultured
astrocytes is around 019 mM suggesting that both the
cytosolic ADH3 and mitochondrial ALDH2 could contribute
to formaldehyde oxidation (Tulpule and Dringen 2012)
Although cultured astrocytes and neurons have compara-
ble rates of formaldehyde clearance the metabolic fate of the
disposed formaldehyde differs between these two types of
neural cells Although astrocytes convert the majority
(gt 90) of formaldehyde to formate that is subsequently
exported from the cells (Tulpule and Dringen 2012) only
about 25 of the formaldehyde cleared by cultured neurons
is detected as extracellular formate (Tulpule et al 2013) The
underlying reason for this difference might be a poor export
of formate from cultured neurons andor a higher capacity of
these cells to further oxidize formate to carbon dioxide
(Fig 1) Although the putative formate exporters GABA-
gated channels (Mason et al 1990) and monocarboxylate
transporter (MCT) 1 (Moschen et al 2012) are expressed in
both astrocytes and neurons (Debernardi et al 2003 Olsen
and Sieghart 2009 Lee et al 2011 Velez-Fort et al 2011)
the expression level of MCT1 in neurons has been reported
to be very low (Debernardi et al 2003) However if poor
export of formate would be the only reason behind the lower extracellular accumulation of this metabolite in cultured
neurons these cells should accumulate large amounts of
formaldehyde-derived formate which is not the case (Tulp-
ule et al 2013) Thus the lower extracellular accumulation
of formaldehyde-derived formate in cultured neurons com-
pared to cultured astrocytes is likely to be predominantly
caused by oxidation of formaldehyde-derived cellular
formate to carbon dioxide The enzymes involved in the
oxidation of 10-formyl THF require NADP+ as electron
acceptor (Krupenko 2009 Krupenko et al 2010) and the
availability of NADP+ in cytosol and mitochondria depends
on the pathways involved in NADPH consumption and
NADPH regeneration As such pathways differ between
astrocytes and neurons (Dringen et al 2007) the NADP+
availability could also contribute to the differences observed
in formate release from astrocytes and neurons that were
exposed to formaldehyde (Tulpule and Dringen 2012
Tulpule et al 2013)
Alterations of the metabolism of braincells upon exposure to formaldehyde
A large number of adverse consequences have been reported
for an exposure of brain cells to formaldehyde in vivo and
Table 1 Formaldehyde-producing and formaldehyde-metabolizing enzymes in the brain
Enzymes
Species
Rat Mouse Human
Formaldehyde generation
ADH1 Martinez et al (2001)
Catalase Zimatkin and Lindros (1996) Schad et al (2003) Meinerz et al (2013) van Horssen et al (2008)
SSAOVAP1 Obata and Yamanaka (2000) Ferrer et al (2002) Unzeta et al (2007)
Valente et al (2012)
LSD1 Zibetti et al (2010) Zhang et al (2010) Zibetti et al (2010)
JHDM Wolf et al (2007) Fukuda et al (2011) Wolf et al (2007)
Formaldehyde oxidation
ADH3 Julia et al (1987) Iborra et al (1992)
Galter et al (2003)
Galter et al (2003) Galter et al (2003)
ALDH2 Guo et al (2013) Alnouti and Klaassen (2008) Stewart et al (1996)
Formate oxidation
MTHFD1 Thigpen et al (1990) MacFarlane et al (2009) Fountoulakis et al (2003)
MTHFD1L Prasannan et al (2003)
ALDH1L1 Neymeyer et al (1997) Anthony and Heintz (2007) Cahoy et al (2008) Oldham et al (2008)
ALDH1L2 Krupenko et al (2010)
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in vitro (Table 2) Recently it was demonstrated that
formaldehyde in the concentration range between 01 mM
and 1 mM strongly affects basal metabolic properties of
cultured astrocytes and neurons that is formaldehyde
stimulates glycolytic 1047298ux and the export of the antioxidative
tripeptide GSH from brain cells
Formaldehyde-stimulated glycolysisAstrocytes are more glycolytic than neurons (Bola~nos et al
2010) a feature which has been attributed to expression of
the glycolysis-promoting enzyme PFKFB3 in astrocytes
(Herrero-Mendez et al 2009) an inhibited pyruvate dehy-
drogenase complex (Halim et al 2010) and a low rate of
NADH shuttling into mitochondria in astrocytes (Berkich
et al 2007 Neves et al 2012) Despite the differences in
basal rates of glucose consumption and lactate release in
cultured astrocytes and neurons application of formaldehyde
signi1047297cantly increases these rates in both types of brain cells
(Tulpule and Dringen 2012 Tulpule et al 2013) However
the extent of stimulation of glycolytic 1047298ux in formaldehyde-
exposed cells compared to the basal condition differs
between the culture types investigated For example at a
formaldehyde concentration of 05 mM the lactate release
and glucose consumption rates were doubled in cultured
neurons (Tulpule et al 2013) while this concentration of
formaldehyde did not affect glycolysis in cultured astrocytes
(Tulpule and Dringen 2012) Astrocytes had to be exposed to
1 mM formaldehyde to elevate glycolysis by 50 (Tulpule
and Dringen 2012)
The accelerated glycolysis in formaldehyde-exposed neu-
ral cells is likely to be caused by the formaldehyde-derived
formate which is known to inhibit mitochondrial cytochrome
c oxidase (Nicholls 1975 Wallace et al 1997) This view is
supported by the observation that incubation of astrocytes
with formaldehyde for 90 min is required for the accelerated
lactate release to persist even after removal of formaldehyde
(Tulpule and Dringen 2012) This long delay most likely
re1047298ects the slow mitochondrial accumulation of formalde-
hyde-derived formate to concentrations that are suf 1047297cient to
inactivate respiration as most of the formate is ef 1047297cientlyexported from astrocytes Moreover the persistent lactate
release of astrocytes exposed to formaldehyde was not
further enhanced by application of azide an inhibitor of
mitochondrial cytochrome c oxidase (Tulpule and Dringen
2012) Thus formaldehyde-derived formate is likely to
stimulate glycolytic 1047298ux as a consequence of an inhibited
respiration as also other inhibitors of respiratory chain
complexes stimulate glycolytic lactate production in cultured
astrocytes and neurons (Pauwels et al 1985 Scheiber and
Dringen 2011)
Formaldehyde-accelerated glutathione export
GSH is an important antioxidant (Lushchak 2012 Schmidt
and Dringen 2012 Lu 2013) that is also involved in the
formaldehyde oxidation catalyzed by ADH3 (Fig 1) Under
basal conditions cultured astrocytes and neurons as well as
cells of the oligodendroglial cell line OLN-93 export GSH
although with variable rates (Tulpule and Dringen 2011
Tulpule et al 2012 2013) Formaldehyde treatment stimu-
lated GSH export from all three types of cultured neural cells
without severely altering the ratio of GSH to glutathione
disul1047297de (GSSG) (Tulpule and Dringen 2011 Tulpule et al
2012 2013) This accelerated GSH export from formalde-
hyde-treated neural cells is mediated by multidrug resistance
Table 2 Consequences of a formaldehyde exposure of rodent brain cells in vivo and in vitro
References
In vivo
Decrease in the number of neuron Gurel et al (2005) Aslan et al (2006) Sarsilmaz et al (2007)Decreased level of GSH Lu et al (2008)
Lowered levels of superoxide dismutase and catalase Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in levels of nitric oxide malondialdehyde
and protein carbonyls
Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in apoptotic events Zararsiz et al (2006 2007)
De1047297cit in memory and learning Pitten et al (2000) Usanmaz et al (2002) Malek et al (2003)
Sorg et al (2004) Lu et al (2008) Turkoglu et al (2008)
Tong et al (2011 2013a b)
In vitro
Elevated glycolysis in neurons and astrocytes Tulpule and Dringen (2012) Tulpule et al (2013)
Mrp1-stimulated GSH export from neurons and astrocytes Tulpule and Dringen (2011) Tulpule et al (2013)
Decreased gl utamate uptake in cultured astrocytes Song et al (2010)
Lower expression of neuronal NMDA receptor subunits Tong et al (2013a)
The articles by Lu et al (2008) Usanmaz et al (2002) and Tong et al (2011) describe data that have been obtained on mice whereas all other
studies were performed on rats or rat brain cells
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protein (Mrp) 1 (Tulpule and Dringen 2011 Tulpule et al
2012 2013) Mrp1 is a member of ATP-binding cassette
transporters and transports besides GSH a wide array of
substrates including GSSG and GSH conjugates (Keppler
2011 Yin and Zhang 2011) The potential of formaldehydeto accelerate GSH export differs between different brain cell
culture types For example exposure to 05 mM formalde-
hyde increased the respective GSH export rates of cultured
astrocytes neurons and OLN-93 cells by 10- 5- and 20-fold
respectively (Tulpule and Dringen 2011 Tulpule et al 2012
2013) However half-maximal cellular GSH depletions were
observed at similar incubation parameters for all types of
neural cells after incubation for 1 h with 03 mM formalde-
hyde (Tulpule and Dringen 2011 Tulpule et al 2012 2013)
Formaldehyde exposure does not impair the capacity of
neural cells to synthesize GSH At least formaldehyde-treated
neurons restored their cellular GSH levels after application of
amino acid precursors for GSH synthesis (Tulpule et al
2013)
The molecular mechanism involved in the formaldehyde-
accelerated Mrp1-mediated GSH export from neural cells is
not resolved so far Since the stimulation of GSH export is
observed within minutes after formaldehyde application
(Tulpule and Dringen 2011 Tulpule et al 2012 2013)
de novo synthesis of Mrp1 is unlikely to explain the
stimulated GSH ef 1047298ux Furthermore the 1047297nding that removal
of formaldehyde instantly decelerates the stimulated GSH
export (Tulpule and Dringen 2011 Tulpule et al 2012
2013) indicates that the mechanism responsible for formal-
dehyde-accelerated GSH export is quickly reversibleAssuming that cellular GSH is the transported Mrp1
substrate (Fig 2a) formaldehyde could stimulate GSH
export by a reversible covalent activation of this transporter
Alternatively a formaldehyde-induced recruitment of intra-
cellular Mrp1 molecules into the cell membrane could
explain the accelerated GSH export Such a reversible
translocation of Mrp1 from the Golgi to the cell surface
has been reported for cultured astrocytes treated with
bilirubin (Gennuso et al 2004)
Mrp1 ef 1047297ciently exports GSH conjugates (Keppler 2011
Yin and Zhang 2011) As the formaldehyde metabolism in
neural cells involves the generation of the GSH conjugatesS-hydroxymethyl GSH and S-formyl GSH (Fig 1) these
conjugates could also serve as substrates of Mrp1 (Fig 2b)
Since both conjugates are known to be labile (Ahmed and
Ahmed 1978 Uotila 1981) they are likely to disintegrate
into GSH and formaldehyde or formate immediately after
being exported
Direct experimental evidence that discriminates between
the potential two mechanisms (Fig 2) that may be involved
in the formaldehyde-induced accelerated GSH export via
Mrp1 is missing so far However determination of the
kinetic parameters for the GSH export from astrocytes
revealed that the K M-values of the basal as well as the
formaldehyde-accelerated GSH export from astrocytes are
identical (about 100 nmolmg or 25 mM) but that the
V max-value for the stimulated GSH export is eightfold higher
than that for the basal GSH export (Tulpule et al 2012)
These data suggest that at least for formaldehyde-treated
astrocytes GSH rather than a GSH conjugate is exported via
Mrp1 since the K M-values of Mrp1 for its substrate GSH are
normally higher than 5 mM while that for GSH conjugates
are below 1 mM (Burg et al 2002 Cole and Deeley 2006
Deeley and Cole 2006)
Application of formaldehyde does not deprive the cells
completely of their GSH and about 5 residual GSH still
remains within neural cells (Tulpule and Dringen 2011Tulpule et al 2012 2013) In cultured astrocytes this low
cellular GSH content represents a residual GSH concentra-
tion of about 04 mM (Dringen and Hamprecht 1998) which
will be suf 1047297cient to drive ADH3-catalyzed GSH-dependent
formaldehyde oxidation since the K M-value of ADH3 for
S-hydroxymethyl GSH is less than 10 lM (Casanova-
Schmitz et al 1984 Heck et al 1990) and this reaction
(a) (b)
Fig 2 Potential mechanisms involved in
formaldehyde-stimulated glutathione (GSH)
export from brain cells (a) Formaldehyde
directlystimulatesMrp1-mediatedGSH export
(b) The GSH conjugates S-hydroxymethyl
GSH andor S-formyl GSH which are
intermediates of cellular formaldehyde
metabolism are exported by Mrp1 The
labile conjugates immediately disintegrate
after export to generate GSH
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involves recycling of GSH (Fig 1) Thus the stimulated
GSH export is unlikely to compromise GSH-dependent
formaldehyde oxidation
Evidence for the role of formaldehyde in pathology
In healthy individuals the formaldehyde concentration in the
blood has been reported to be around 01 mM (Heck and
Casanova 2004) while that in the brain is about 02 mM
(hippocampus) and 04 mM (cortex) (Tong et al 2013a)
These levels of formaldehyde represent the normal phy-
siological balance between formaldehyde-generating and
formaldehyde-disposing processes However an increased
activity of formaldehyde-generating enzymes or an acute
exposure to high amounts of exogenous formaldehyde
without a concurrent elevation in the capacity to clear
formaldehyde will raise formaldehyde level in the body and
will lead to formaldehyde stress (He et al 2010) Indeed an
increased expressionactivity of the formaldehyde-generating
enzymes VAP1SSAO LSD1 and JHDM has been reported
for various diseases (Table 3) While a broad spectrum of
pathological conditions are associated with elevated levels of
VAP1SSAO an increase in the expression of the histone
demethylases has especially been observed in different types
of cancer (Table 3) The elevated expression of formalde-
hyde-generating enzymes is accompanied by increased
formaldehyde levels in diabetic rats (Tong et al 2013a) in
cancer tissue (Tong et al 2010) and in some human cancer
cell lines (Kato et al 2001 Tong et al 2010)
Increased expression of formaldehyde-generating enzymes
(Table 3) as well as elevated formaldehyde levels have also
been reported in brains of patients suffering from neurode-
generative diseases like Alzheimer rsquos disease (AD) or multi-
ple sclerosis (MS) (Khokhlov et al 1989 cited in Miao andHe 2012 Tong et al 2011 2013a) Some hypotheses have
been postulated that link the increase in formaldehyde level
to neuropathology For example some human subjects who
suffered from methanol poisoning developed symptoms of
MS which has been discussed to be an effect of methanol
oxidation to formaldehyde and the subsequent modi1047297cation
of proteins resulting in an immune reaction (Schwyzer and
Henzi 1983 Henzi 1984) Along that line it was discussed
that formaldehyde methylates proteins like tau (in AD) or
myelin basic protein (in MS) which in turn elicits an immune
response by the body that is characteristic for these diseases
(Monte 2010 Lu et al 2013) Also inhibition of SSAO in a
murine model of MS has been shown to reduce the incidence
and severity of this disease (Wang et al 2006) which could
at least partly be the consequence of a lowered formaldehyde
generation Moreover formaldehyde exposure has been
implicated to be a risk factor for the development of
amyotrophic lateral sclerosis (Weisskopf et al 2009) a
disease that is characterized by degeneration of motor
neurons (Kiernan et al 2011)
Formaldehyde-induced alterations in neuralmetabolism as potential contributors toneurodegeneration
Figure 3 summarizes the current knowledge on formalde-
hyde metabolism and on formaldehyde-induced alterations in
the glucose and GSH metabolism of neural cells The
potential of cultured brain cells to ef 1047297ciently metabolize
formaldehyde suggests that also the cells in brain deal quite
well with the moderate amounts of formaldehyde that are
generated under physiological conditions Similar to liver
cells brain cells are likely to use both cytosolic and
mitochondrial pathways for formaldehyde oxidation to
formate and further to carbon dioxide (Figs 1 and 3)
Cultured brain cells ef 1047297ciently produce and export glyco-
lytically generated lactate and also release GSH into the
medium although the basal rates of glycolysis and GSH
export differ between different types of neural cells (Tulpule
and Dringen 2011 2012 Tulpule et al 2012 2013) These
pathways are not affected by low concentrations of formal-
dehyde but as soon as formaldehyde levels are increased in
pathological conditions an accelerated generation of formate
is likely to stimulate glycolytic 1047298ux by inhibition of the
mitochondrial respiration (Fig 3) In addition an excess of
formaldehyde deprives brain cells of GSH by stimulating
Mrp1-mediated GSH export (Fig 3) Although caution should
be exercised while extrapolating in vitro data to the situation
in the brain a speculation on potential consequences of
Table 3 Elevation in expression or activity of formaldehyde-generat-
ing enzymes in human diseases
Enzyme Disease References
SSAOVAP1 Alzheimer rsquos disease Ferrer et al (2002) del Mar
Hernandez et al (2005)
Unzeta et al (2007)
Multiple sclerosis Airas et al (2006)
Heart disease Boomsma et al (2000 2005)
Diabetes mellitus
and diabetic
complications
Meszaros et al (1999)
Gr euroonvall-Nordquist
et al (2001) Karadi et al(2002) Boomsma et al
(2005) Obata (2006)
Chronic liver disease Kurkijarvi et al (2000)
LSD1JHDM Sarcoma Schildhaus et al (2011)
Bennani-Baiti et al (2012)
Peripheral nerve
sheath tumor
Schildhaus et al (2011)
Neuroblastoma Schulte et al (2009)
Bladder cancer Hayami et al (2010 2011)
Breast cancer Lim et al (2010)
Prost ate cancer Kahl et al (2006) Xiang
et al (2007)
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 13
7212019 Journal of Neurochemistry
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elevated formaldehyde levels in brain on the cellular metab-
olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of
cultured brain cells (01 ndash 1 mM) are in the concentration
range reported for the normal brain (02 ndash 04 mM) Thus mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig 4 Astrocytes and neurons in brain are likely to
ef 1047297ciently metabolize an excess of formaldehyde as also
reported for brain homogenates (Iborra et al 1992) Subse-
quently the formate generated from formaldehyde is either
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain
cells to at least transiently meet their energy demand
However prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al 2007) Besides this impairment of energy
metabolism formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003 Rose 2010) which would subsequently
induce astrocytic swelling impairment of neuronal signal
Fig 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the
generated formate is exported while a fraction is further oxidized to
carbon dioxide Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites
Fig 4 Potential consequences of an
excess of formaldehyde in brain Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed
indirect consequences (dark gray squares)
that 1047297nally lead to the adverse effects
reported for formaldehyde exposure
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
14 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 15
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Conflict of interest
The authors have no con1047298ict of interest to declare
References
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behavioral effects of formaldehyde in the rat J Exp Anim Sci 42
160 ndash 170
del Mar Hernandez M Esteban M Szabo P Boada M and Unzeta M
(2005) Human plasma semicarbazide sensitive amine oxidase
(SSAO) b-amyloid protein and aging Neurosci Lett 384183 ndash 187
Martinez S E Vaglenova J Sabria J Martinez M C Farres J and
Pares X (2001) Distribution of alcohol dehydrogenase mRNA in
the rat central nervous system - consequences for brain ethanol and
retinoid metabolism Eur J Biochem 268 5045 ndash 5056Mason M J Mattsson K Pasternack M Voipio J and Kaila K (1990)
Postsynaptic fall in intracellular pH and increase in surface pH
caused by ef 1047298ux of formate and acetate anions through GABA-
gated channels in cray1047297sh muscle-1047297bers Neuroscience 34 359 ndash
368
Meinerz D F Comprasi B Allebrandt J et al (2013) Sub-acute
administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido)
succinate induces toxicity and oxidative stress in mice unexpected
effects of N-acetylcysteine Springerplus 2 182
Meszaros Z Szombathy T Raimondi L Karadi I Romics L and
Magyar K (1999) Elevated serum semicarbazide-sensitive amine
oxidase activity in non-insulin-dependent diabetes mellitus
correlation with body mass index and serum triglyceride
Metabolism 48 113 ndash 117
Metz B Kersten G F Hoogerhout P et al (2004) Identi1047297cation of formaldehyde-induced modi1047297cations in proteins reactions with
model peptides J Biol Chem 279 6235 ndash 6243
Metz B Kersten G F Baart G J de Jong A Meiring H ten Hove J
van Steenbergen M J Hennink W E Crommelin D J and
Jiskoot W (2006) Identi1047297cation of formaldehyde-induced
modi1047297cations in proteins reactions with insulin Bioconjug
Chem 17 815 ndash 822
Miao J and He R (2012) Chronic formaldehyde-mediated impairments
and age-related dementia in Neurodegeneration (Martin L M and
Loh S H Y eds) pp 59 ndash 76 InTech doi 10577234949
Monte W C (2010) Methanol a chemical Trojan horse as the root of the
inscrutable U Med Hypotheses 74 493 ndash 496
Moschen I Broer A Galic S Lang F and Broer S (2012) Signi1047297cance
of short chain fatty acid transport by members of the
monocarboxylate transporter family (MCT) Neurochem Res 372562 ndash 2568
Mukherjee S and Manahan-Vaughan D (2013) Role of metabotropic
glutamate receptors in persistent forms of hippocampal plasticity
and learning Neuropharmacology 66 65 ndash 81
Nazarian A Hermannsson B J Muller J Zurakowski D and Snyder
B D (2009) Effects of tissue preservation on murine bone
mechanical properties J Biomech 42 82 ndash 86
Neves A Costalat R and Pellerin L (2012) Determinants of brain
cell metabolic phenotypes and energy substrate utilization unraveled
with a modeling approach PLoS Comput Biol 8 e1002686
Neymeyer V Tephly T R and Miller M W (1997) Folate and 10-
formyltetrahydrofolate dehydrogenase (FDH) expression in the
central nervous system of the mature rat Brain Res 766 195 ndash 204
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
18 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1315
Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase
Biochem Biophys Res Commun 67 610 ndash 616
Nishimura M and Naito S (2006) Tissue-speci1047297c mRNA expression
pro1047297les of human phase I metabolizing enzymes except for
cytochrome P450 and phase II metabolizing enzymes Drug
Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
(SSAO) activity a review Life Sci 79 417 ndash 422
Obata T and Yamanaka Y (2000) Evidence for existence of
immobilization stress-inducible semicarbazide-sensitive amine
oxidase inhibitor in rat brain cytosol Neurosci Lett 296 58 ndash 60
Oldham M C Konopka G Iwamoto K Langfelder P Kato T
Horvath S and Geschwind D (2008) Functional organization of
the transcriptome in the human brain Nat Neurosci 11 1271 ndash
1282
Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide
diversity of function and pharmacology Neuropharmacology 56
141 ndash 148
OrsquoSullivan J Unzeta M Healy J OrsquoSullivan M I Davey G and
Tipton K F (2004) Semicarbazide-sensitive amine oxidases
enzymes with quite a lot to do Neurotoxicology 25 303 ndash 315Oyama Y Sakai H Arata T Okano Y Akaike N Sakai K and Noda
K (2002) Cytotoxic effects of methanol formaldehyde and
formate on dissociated rat thymocytes a possibility of aspartame
toxicity Cell Biol Toxicol 18 43 ndash 50
Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D
(2011) Energy failure in multiple sclerosis and its investigation
using MR techniques J Neurol 258 2113 ndash 2127
Parnetti L Reboldi G P and Gallai V (2000) Cerebrospinal 1047298uid
pyruvate levels in Alzheimer rsquos disease and vascular dementia
Neurology 54 735 ndash 737
Pauwels P J Opperdoes F R and Trouet A (1985) Effects of
antimycin glucose deprivation and serum on cultures of neurons
astrocytes and neuroblastoma cells J Neurochem 44 143 ndash 148
Pitten F A Kramer A Herrmann K Breme I and Koch S (2000)
Formaldehyde neurotoxicity in animal experiments Pathol ResPract 196 193 ndash 198
Prasannan P Pike S Peng K Shane B and Appling D R (2003)
Human mitochondrial C1-tetrahydrofolate synthase gene structure
tissue distribution of the mRNA and immunolocalization in
Chinese hamster ovary cells J Biol Chem 278 43178 ndash 43187
Regan R F and Guo Y P (1999a) Extracellular reduced glutathione
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glucose deprivation Brain Res 817 145 ndash 150
Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
high concentrations of extracellular reduced glutathione
Neuroscience 91 463 ndash 470
Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
Merillon J M and Monti J P (2011) Neuroprotective properties
of resveratrol and derivatives Ann N Y Acad Sci 1215 103 ndash
108Rose C F (2010) Increase brain lactate in hepatic encephalopathy cause
or consequence Neurochem Int 57 389 ndash 394
Ross J M Oberg J Brene S et al (2010) High brain lactate is a
hallmark of aging and caused by a shift in the lactate
dehydrogenase AB ratio Proc Natl Acad Sci USA 107
20087 ndash 20092
Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
indoor environment Chem Rev 110 2536 ndash 2572
Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
Ozen Q A Turgut M and Bas O (2007) Effects of postnatal
formaldehyde exposure on pyramidal cell number volume of cell
layer in hippocampus and hemisphere in the rat a stereological
study Brain Res 1145 157 ndash 167
Sasseville D (2004) Hypersensitivity to preservatives Dermatol Ther
17 251 ndash 263
Schad A Fahimi H D Volkl A and Baumgart E (2003) Expression
of catalase mRNA and protein in adult rat brain detectionby nonradioactive in situ hybridization with signal ampli1047297cation
by catalyzed reporter deposition (ISH-CAR D) and
immunohistochemistry (IHC)immuno1047298uorescence (IF) J
Histochem Cytochem 51 751 ndash 760
Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux
in cultured astrocytes Neurochem Res 36 894 ndash 903
Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c
demethylase 1 is highly expressed in solitary 1047297brous tumors
synovial sarcomas rhabdomyosarcomas desmoplastic small round
cell tumors and malignant peripheral nerve sheath tumors Hum
Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
1029 ndash 1050 Neural Metabolism in vivo Springer New York
Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
neuroblastoma implications for therapy Cancer Res 69 2065 ndash
2071
Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
by 2-step demyelination Med Hypotheses 12 129 ndash 142
Skrzydlewska E (2003) Toxicological and metabolic consequences of
methanol poisoning Toxicol Mech Methods 13 277 ndash 293
Smith D J and Vainio P J (2007) Targeting vascular adhesion protein-
1 to treat autoimmune and in1047298ammatory diseases Ann N Y Acad
Sci 1110 382 ndash 388
Sohal R S and Orr W C (2012) The redox stress hypothesis of aging
Free Radic Biol Med 52 539 ndash 555
Song M S Baker G B Dursun S M and Todd K G (2010) The
antidepressant phenelzine protects neurons and astrocytes
against formaldehyde-induced toxicity J Neurochem 1141405 ndash 1413
Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
Ilhan N (2008) The effects of inhaled formaldehyde on oxidant and
antioxidant systems of rat cerebellum during the postnatal
development process Toxicol Mech Methods 18 569 ndash 574
Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
formaldehyde on the nervous system Rev Environ Contam
Toxicol 203 105 ndash 118
Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
formaldehyde exposure produces enhanced fear conditioning to
odor in male but not female rats Brain Res 1008 11 ndash 19
Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
(2009) The janus face of alcohol dehydrogenase 3 Chem Biol
Interact 178 29 ndash 35
Staub F Peters J Kempski O Schneider G H Schurer Land Baethmann A (1993) Swelling of glial cells in lactacidosis
and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash
74
Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
less support implications for Alzheimer rsquos disease Neurobiol
Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
P Cuenod M and Do K Q (2010) Redox dysregulation affects
the ventral but not dorsal hippocampus impairment of
parvalbumin neurons gamma oscillations and related behaviors
J Neurosci 30 2547 ndash 2558
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 19
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1415
Stewart M J Malek K and Crabb D W (1996) Distribution of
messenger RNAs for aldehyde dehydrogenase 1 aldehyde
dehydrogenase 2 and aldehyde dehydrogenase 5 in human
tissues J Investig Med 44 42 ndash 46
Sullivan P G and Brown M R (2005) Mitochondrial aging and
dysfunction in Alzheimer rsquos disease Prog Neuropsychopharmacol
Biol Psychiatry 29 407 ndash 410
Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
Magistretti P J and Alberini C M (2011) Astrocyte-neuron
lactate transport is required for long-term memory formation Cell
144 810 ndash 823
Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
and health effects Environ Int 35 1210 ndash 1224
Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
neurotoxicity to PC12 cells involving inhibition of paraoxonase-1
expression and activity Clin Exp Pharmacol Physiol 38 208 ndash
214
Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
1041
Thigpen A E West M G and Appling D R (1990) Rat C1-
tetrahydrofolate synthase cDNA isolation tissue-speci1047297c levels of
the mRNA and expression of the protein in yeast J Biol Chem
265 7907 ndash 7913
Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
dehydrogenase beyond phase I metabolism Toxicol Lett 193
1 ndash 3
Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev
Nutr 30 57 ndash 81
Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
formaldehyde and acidic microenvironment synergistically induce
bone cancer pain PLoS ONE 5 e10234
Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
inversely correlated to mini mental state examination scores in
senile dementia Neurobiol Aging 32 31 ndash 41
Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
R (2013a) Accumulated hippocampal formaldehyde induces age-
dependent memory decline Age (Dordr) 35 583 ndash 596
Tong Z Han C Luo W et al (2013b) Aging-associated excess
formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635
Tulpule K and Dringen R (2012) Formate generated by cellular
oxidation of formaldehyde accelerates the glycolytic 1047298ux in
cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
Neurochem Int 61 1302 ndash 1313
Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
metabolism and formaldehyde-induced stimulation of lactate
production and glutathione export in cultured neurons
J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
performance study Erciyes Med J 30 211 ndash 217
Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74
Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
vasculature pathological synergy of Alzheimer rsquos disease and
diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
(1997) Mitochondria-mediated cell injury Symposium overview
Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
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formaldehyde (01 ndash 04 mM) that are found in body 1047298uids
and tissues under normal and pathological conditions (Heck
and Casanova 2004 Tong et al 2013a)
Endogenous and exogenous sources of formaldehyde
Formaldehyde exposure is caused by the generation of this
aldehyde within the body and can also be a consequence of
contact with elevated levels of environmental formaldehyde
(Fig 1) Some of the endogenous enzymatic reactions that
generate formaldehyde as well as exogenous sources of
formaldehyde are described below
Formaldehyde is the oxidation product of methanol This
alcohol can be generated within the body by hydrolysis of
protein carboxymethyl esters either non-enzymatically or
catalyzed by methylesterases (Lee et al 2008) In addition
accidental or intentional intake of methanol will further
expose the body to this alcohol In cells methanol is oxidized
to formaldehyde by alcohol dehydrogenase (ADH) 1 by
catalase or by a non-enzymatic reaction of methanol with
hydroxyl radicals (Harris et al 2003 MacAllister et al
2011) In humans and primates ADH1 appears to be
predominately responsible for methanol oxidation while
the majority of methanol oxidation in rats has been reported
to be mediated by catalase (Tephly 1991 Skrzydlewska
2003)
Another endogenous source of formaldehyde are semicar-
bazide-sensitive amine oxidases (SSAO) which represent agroup of copper-containing amine oxidases that are inhibited
by semicarbazide and most of them contain topa-quinone at
their catalytic centre (Jalkanen and Salmi 2001 Yu et al
2003) Oxidative deamination of methylamine by SSAO
generates formaldehyde together with ammonia and hydro-
gen peroxide (Yu et al 2003 OrsquoSullivan et al 2004) In
mammals SSAO are either membrane-associated or circulate
in a soluble form in the vascular system (Jalkanen and Salmi
2001) Among the SSAO the vascular adhesion protein
(VAP) 1 is one of the most extensively studied members of
this group of enzymes (Smith and Vainio 2007 Jalkanen and
Salmi 2008)
Formaldehyde is also generated as by-product of reactions
catalyzed by lysine-speci1047297c demethylase (LSD) 1 and JmjC
domain-containing histone demethylases (JHDM) (Cloos
et al 2008 Hou and Yu 2010) These enzymes remove
methyl groups from lysine residues in histones thereby
altering the chromatin structure (Cheng and Zhang 2007
Cloos et al 2008 Hou and Yu 2010 Izzo and Schneider
2010) LSD1 is a 1047298avin-containing enzyme that selectively
demethylates the mono- or dimethylated lysine residue in
position 4 of histone H3 (Forneris et al 2009 Hou and Yu
2010) On the other hand JHDM can remove methyl groups
from mono- di- or trimethylated lysine residues and require
Fe2+
and a-ketoglutarate as cofactors (Cloos et al 2008 Houand Yu 2010)
In addition to endogenous sources the body can also
encounter environmental formaldehyde since a number of
commonly used products contain either formaldehyde or
formaldehyde-releasing substances (Sasseville 2004
de Groot et al 2009) Some examples of such products are
construction materials agricultural fertilizers fumigants
paints cosmetics antiperspirants polish cleaning agents
and toiletries (Sasseville 2004 de Groot et al 2009 2010)
In addition formaldehyde can be produced and released from
burning of wood coal tobacco natural gas and kerosene
(de Groot et al 2009 Laitinen et al 2010) Moreover foods
like coffee cod1047297sh meat poultry and maple syrup naturally
contain formaldehyde (Dhareshwar and Stella 2008 de
Groot et al 2009) Thus this ubiquitously present compound
can enter the human body by inhalation ingestion or entry
through the skin
One pertinent question is whether exogenous formalde-
hyde can pose a big threat to the central nervous system by
entering the blood and ultimately reaching the brain after
crossing the blood ndash brain barrier In healthy individuals the
formaldehyde concentration in the blood is around 01 mM
(Heck and Casanova 2004) and that in the brain is
02 ndash 04 mM (Tong et al 2013a) Inhalation of moderate
Fig 1 Endogenous and exogenous sources of formaldehyde (HCHO)
and pathways involved in cellular formaldehyde disposal For details
see text ADH alcohol dehydrogenase ALDH aldehyde dehydroge-
nase cy cytosolic JHDM JmjC domain-containing histone demeth-
ylases LSD lysine-speci1047297c demethylase mt mitochondrial MTHFD
methylene tetrahydrofolate dehydrogenase SSAO semicarbazide-
sensitive amine oxidases VAP vascular adhesion protein
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
8 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 315
doses of formaldehyde does not severely increase the
formaldehyde level in blood (Heck et al 1985 Franks
2005) This is expected as the formaldehyde-oxidizing
enzymes ADH3 and aldehyde dehydrogenase (ALDH) 2
(Fig 1) are ubiquitously expressed in all tissues (Nishimuraand Naito 2006 Alnouti and Klaassen 2008) and will
quickly clear a low excess of environmentally derived
formaldehyde However exposure to high concentrations of
exogenous formaldehyde that exceeds the peripheral form-
aldehyde oxidation capacity will elevate the normal tolerable
concentration of formaldehyde in the blood and could lead
to neural damage Indeed exposure to exogenous formal-
dehyde has been reported to cause neurotoxicity in humans
and animals and the extent of damage depends on the dose
of formaldehyde and the duration of the exposure (Kilburn
et al 1985a b Songur et al 2008 2010) Especially
individuals who carry functional polymorphisms in the
genes encoding for formaldehyde-metabolizing enzymes
ADH3 or ALDH2 which are discussed to be associated with
reduced formaldehyde-oxidizing capacity (Hedberg et al
2001 Wang et al 2002) may be more vulnerable to
neural damage by endogenously generated or environmental
formaldehyde
Metabolism of formaldehyde
Despite of the multiple endogenous and exogenous sources
of formaldehyde a low physiological level of formaldehyde
in body 1047298uids and tissue is maintained by the continuous
action of cellular formaldehyde-metabolizing enzymes(Fig 1) ADH1 is considered to play a negligible role in
formaldehyde reduction to methanol because of its very high
KM-value for formaldehyde (about 30 mM) (Skrzydlewska
2003) The formaldehyde oxidation product formate is
generated by two independent pathways that are mediated
by either the mitochondrial ALDH2 or the cytosolic ADH3
(Teng et al 2001 Friedenson 2011 MacAllister et al
2011) ADH3 also known as glutathione (GSH)-dependent
formaldehyde dehydrogenase oxidizes formaldehyde to
formate in a two-step process (Harris et al 2003 Staab
et al 2009 Thompson et al 2010 MacAllister et al 2011)
In the 1047297rst step GSH reacts with formaldehyde in an
enzyme-independent manner to form S-hydroxymethyl GSH
that is subsequently used as ADH3 substrate to generate S-
formyl GSH (Harris et al 2003 Staab et al 2009 Thomp-
son et al 2010 MacAllister et al 2011) The conjugate S-
formyl GSH is hydrolyzed by a thiolase to generate formate
and GSH (Teng et al 2001 Harris et al 2003 MacAllister
et al 2011) Unlike ADH3 the reaction catalyzed by
ALDH2 is a single-step GSH-independent process (Teng
et al 2001 MacAllister et al 2011) Since ADH3 has a
very low KM-value for S-hydroxymethyl GSH (less than
10 lM) compared to that of ALDH2 for formaldehyde (02 ndash
05 mM) (Casanova-Schmitz et al 1984 Heck et al 1990)
ADH3 is likely to be especially important for the oxidation
of low concentrations of formaldehyde
The formate generated by formaldehyde oxidation can
undergo further oxidization to carbon dioxide in a metabolic
pathway involving tetrahydrofolate (THF) wherein formateis 1047297rst converted to 10-formyl THF (Fig 1) in an ATP-
dependent reaction (Skrzydlewska 2003 Krupenko 2009
Krupenko et al 2010) This reaction is catalyzed either by
the cytosolic methylene tetrahydrofolate dehydrogenase
(MTHFD) 1 or by its mitochondrial isoform MTHFD1L
(Tibbetts and Appling 2010) 10-formyl THF is subsequently
oxidized by the cytosolic 10-formyl THF dehydrogenase
also known as ALDH1L1 or its mitochondrial isoform
ALDH1L2 to carbon dioxide Both enzymes use NADP+ as a
co-factor and regenerate THF (Skrzydlewska 2003 Kru-
penko 2009 Krupenko et al 2010) Although formate
oxidation takes place predominantly by the THF-dependent
pathway catalase-mediated oxidation of formate has also
been reported (Cook et al 2001 Skrzydlewska 2003)
Formaldehyde metabolism (Fig 1) is best studied for the
liver (Skrzydlewska 2003 Tibbetts and Appling 2010) but it
is very likely that other organs including the brain will also
use the enzymatic pathways that are well known for
formaldehyde metabolism in liver In brain at least all the
enzymes required for complete formaldehyde oxidation are
expressed (Table 1)
Differences in the rate of formaldehyde metabolism have
been described between species for the formaldehyde
metabolism For example formate is metabolized at a slower
rate in the liver of monkeys and humans compared to ratspartly because rats have a higher hepatic THF content
(Tephly 1991 Skrzydlewska 2003) Also species-speci1047297c
differences in the kinetic parameters of the enzymes involved
in formaldehyde metabolism may contribute to the different
rates of formaldehyde oxidation observed and subsequently
may determine the consequences of an exposure to formal-
dehyde andor it metabolites
Generation and oxidation of formaldehydein brain cells
Several reports have demonstrated that the enzymes required
to produce or metabolize formaldehyde are expressed in the
brain on the mRNA or protein level (Table 1) Of these
enzymes only the expression of ADH1 in the brain has been
controversially discussed since this dehydrogenase was not
detected in brain by some investigators (Julia et al 1987
Galter et al 2003) Despite the presence of ADH1 mRNA in
cultured neural cells methanol generation was not found for
formaldehyde-exposed cultured brain cells (Tulpule and
Dringen 2012 Tulpule et al 2013) suggesting that oxida-
tion to formate is the preferred pathway of formaldehyde
metabolism in brain cells Cultured astrocytes and neurons
contain the mRNAs for SSAO and LSD1 as well as for the
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 9
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 415
enzymes involved in formaldehyde metabolism (Tulpule and
Dringen 2012 Tulpule et al 2013) These studies indicate
that formaldehyde may be produced locally in the brain and
that among the different types of brain cells at least astrocytes
and neurons have the potential to generate and oxidize
formaldehyde
Acute formaldehyde exposure in concentrations of up to
1 mM for up to 3 h does not cause severe toxicity in cultured
astrocytes or neurons (Song et al 2010 Tulpule and Dringen2011 2012 Tulpule et al 2013) A rapid metabolism of
cellular formaldehyde may contribute to the resistance of
cultured brain cells to formaldehyde toxicity since formal-
dehyde has been reported to be more cytotoxic than its
metabolites methanol and formate (Oyama et al 2002 Lee
et al 2008) Both cultured astrocytes and neurons clear
exogenously applied formaldehyde with a similar rate of
around 02 lmol(h 9 mg) (Tulpule and Dringen 2012
Tulpule et al 2013) which is about 20 of the formaldehyde
oxidation rate reported for liver cells (Dicker and Cederbaum
1984) The K M-value for formaldehyde clearance by cultured
astrocytes is around 019 mM suggesting that both the
cytosolic ADH3 and mitochondrial ALDH2 could contribute
to formaldehyde oxidation (Tulpule and Dringen 2012)
Although cultured astrocytes and neurons have compara-
ble rates of formaldehyde clearance the metabolic fate of the
disposed formaldehyde differs between these two types of
neural cells Although astrocytes convert the majority
(gt 90) of formaldehyde to formate that is subsequently
exported from the cells (Tulpule and Dringen 2012) only
about 25 of the formaldehyde cleared by cultured neurons
is detected as extracellular formate (Tulpule et al 2013) The
underlying reason for this difference might be a poor export
of formate from cultured neurons andor a higher capacity of
these cells to further oxidize formate to carbon dioxide
(Fig 1) Although the putative formate exporters GABA-
gated channels (Mason et al 1990) and monocarboxylate
transporter (MCT) 1 (Moschen et al 2012) are expressed in
both astrocytes and neurons (Debernardi et al 2003 Olsen
and Sieghart 2009 Lee et al 2011 Velez-Fort et al 2011)
the expression level of MCT1 in neurons has been reported
to be very low (Debernardi et al 2003) However if poor
export of formate would be the only reason behind the lower extracellular accumulation of this metabolite in cultured
neurons these cells should accumulate large amounts of
formaldehyde-derived formate which is not the case (Tulp-
ule et al 2013) Thus the lower extracellular accumulation
of formaldehyde-derived formate in cultured neurons com-
pared to cultured astrocytes is likely to be predominantly
caused by oxidation of formaldehyde-derived cellular
formate to carbon dioxide The enzymes involved in the
oxidation of 10-formyl THF require NADP+ as electron
acceptor (Krupenko 2009 Krupenko et al 2010) and the
availability of NADP+ in cytosol and mitochondria depends
on the pathways involved in NADPH consumption and
NADPH regeneration As such pathways differ between
astrocytes and neurons (Dringen et al 2007) the NADP+
availability could also contribute to the differences observed
in formate release from astrocytes and neurons that were
exposed to formaldehyde (Tulpule and Dringen 2012
Tulpule et al 2013)
Alterations of the metabolism of braincells upon exposure to formaldehyde
A large number of adverse consequences have been reported
for an exposure of brain cells to formaldehyde in vivo and
Table 1 Formaldehyde-producing and formaldehyde-metabolizing enzymes in the brain
Enzymes
Species
Rat Mouse Human
Formaldehyde generation
ADH1 Martinez et al (2001)
Catalase Zimatkin and Lindros (1996) Schad et al (2003) Meinerz et al (2013) van Horssen et al (2008)
SSAOVAP1 Obata and Yamanaka (2000) Ferrer et al (2002) Unzeta et al (2007)
Valente et al (2012)
LSD1 Zibetti et al (2010) Zhang et al (2010) Zibetti et al (2010)
JHDM Wolf et al (2007) Fukuda et al (2011) Wolf et al (2007)
Formaldehyde oxidation
ADH3 Julia et al (1987) Iborra et al (1992)
Galter et al (2003)
Galter et al (2003) Galter et al (2003)
ALDH2 Guo et al (2013) Alnouti and Klaassen (2008) Stewart et al (1996)
Formate oxidation
MTHFD1 Thigpen et al (1990) MacFarlane et al (2009) Fountoulakis et al (2003)
MTHFD1L Prasannan et al (2003)
ALDH1L1 Neymeyer et al (1997) Anthony and Heintz (2007) Cahoy et al (2008) Oldham et al (2008)
ALDH1L2 Krupenko et al (2010)
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in vitro (Table 2) Recently it was demonstrated that
formaldehyde in the concentration range between 01 mM
and 1 mM strongly affects basal metabolic properties of
cultured astrocytes and neurons that is formaldehyde
stimulates glycolytic 1047298ux and the export of the antioxidative
tripeptide GSH from brain cells
Formaldehyde-stimulated glycolysisAstrocytes are more glycolytic than neurons (Bola~nos et al
2010) a feature which has been attributed to expression of
the glycolysis-promoting enzyme PFKFB3 in astrocytes
(Herrero-Mendez et al 2009) an inhibited pyruvate dehy-
drogenase complex (Halim et al 2010) and a low rate of
NADH shuttling into mitochondria in astrocytes (Berkich
et al 2007 Neves et al 2012) Despite the differences in
basal rates of glucose consumption and lactate release in
cultured astrocytes and neurons application of formaldehyde
signi1047297cantly increases these rates in both types of brain cells
(Tulpule and Dringen 2012 Tulpule et al 2013) However
the extent of stimulation of glycolytic 1047298ux in formaldehyde-
exposed cells compared to the basal condition differs
between the culture types investigated For example at a
formaldehyde concentration of 05 mM the lactate release
and glucose consumption rates were doubled in cultured
neurons (Tulpule et al 2013) while this concentration of
formaldehyde did not affect glycolysis in cultured astrocytes
(Tulpule and Dringen 2012) Astrocytes had to be exposed to
1 mM formaldehyde to elevate glycolysis by 50 (Tulpule
and Dringen 2012)
The accelerated glycolysis in formaldehyde-exposed neu-
ral cells is likely to be caused by the formaldehyde-derived
formate which is known to inhibit mitochondrial cytochrome
c oxidase (Nicholls 1975 Wallace et al 1997) This view is
supported by the observation that incubation of astrocytes
with formaldehyde for 90 min is required for the accelerated
lactate release to persist even after removal of formaldehyde
(Tulpule and Dringen 2012) This long delay most likely
re1047298ects the slow mitochondrial accumulation of formalde-
hyde-derived formate to concentrations that are suf 1047297cient to
inactivate respiration as most of the formate is ef 1047297cientlyexported from astrocytes Moreover the persistent lactate
release of astrocytes exposed to formaldehyde was not
further enhanced by application of azide an inhibitor of
mitochondrial cytochrome c oxidase (Tulpule and Dringen
2012) Thus formaldehyde-derived formate is likely to
stimulate glycolytic 1047298ux as a consequence of an inhibited
respiration as also other inhibitors of respiratory chain
complexes stimulate glycolytic lactate production in cultured
astrocytes and neurons (Pauwels et al 1985 Scheiber and
Dringen 2011)
Formaldehyde-accelerated glutathione export
GSH is an important antioxidant (Lushchak 2012 Schmidt
and Dringen 2012 Lu 2013) that is also involved in the
formaldehyde oxidation catalyzed by ADH3 (Fig 1) Under
basal conditions cultured astrocytes and neurons as well as
cells of the oligodendroglial cell line OLN-93 export GSH
although with variable rates (Tulpule and Dringen 2011
Tulpule et al 2012 2013) Formaldehyde treatment stimu-
lated GSH export from all three types of cultured neural cells
without severely altering the ratio of GSH to glutathione
disul1047297de (GSSG) (Tulpule and Dringen 2011 Tulpule et al
2012 2013) This accelerated GSH export from formalde-
hyde-treated neural cells is mediated by multidrug resistance
Table 2 Consequences of a formaldehyde exposure of rodent brain cells in vivo and in vitro
References
In vivo
Decrease in the number of neuron Gurel et al (2005) Aslan et al (2006) Sarsilmaz et al (2007)Decreased level of GSH Lu et al (2008)
Lowered levels of superoxide dismutase and catalase Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in levels of nitric oxide malondialdehyde
and protein carbonyls
Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in apoptotic events Zararsiz et al (2006 2007)
De1047297cit in memory and learning Pitten et al (2000) Usanmaz et al (2002) Malek et al (2003)
Sorg et al (2004) Lu et al (2008) Turkoglu et al (2008)
Tong et al (2011 2013a b)
In vitro
Elevated glycolysis in neurons and astrocytes Tulpule and Dringen (2012) Tulpule et al (2013)
Mrp1-stimulated GSH export from neurons and astrocytes Tulpule and Dringen (2011) Tulpule et al (2013)
Decreased gl utamate uptake in cultured astrocytes Song et al (2010)
Lower expression of neuronal NMDA receptor subunits Tong et al (2013a)
The articles by Lu et al (2008) Usanmaz et al (2002) and Tong et al (2011) describe data that have been obtained on mice whereas all other
studies were performed on rats or rat brain cells
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protein (Mrp) 1 (Tulpule and Dringen 2011 Tulpule et al
2012 2013) Mrp1 is a member of ATP-binding cassette
transporters and transports besides GSH a wide array of
substrates including GSSG and GSH conjugates (Keppler
2011 Yin and Zhang 2011) The potential of formaldehydeto accelerate GSH export differs between different brain cell
culture types For example exposure to 05 mM formalde-
hyde increased the respective GSH export rates of cultured
astrocytes neurons and OLN-93 cells by 10- 5- and 20-fold
respectively (Tulpule and Dringen 2011 Tulpule et al 2012
2013) However half-maximal cellular GSH depletions were
observed at similar incubation parameters for all types of
neural cells after incubation for 1 h with 03 mM formalde-
hyde (Tulpule and Dringen 2011 Tulpule et al 2012 2013)
Formaldehyde exposure does not impair the capacity of
neural cells to synthesize GSH At least formaldehyde-treated
neurons restored their cellular GSH levels after application of
amino acid precursors for GSH synthesis (Tulpule et al
2013)
The molecular mechanism involved in the formaldehyde-
accelerated Mrp1-mediated GSH export from neural cells is
not resolved so far Since the stimulation of GSH export is
observed within minutes after formaldehyde application
(Tulpule and Dringen 2011 Tulpule et al 2012 2013)
de novo synthesis of Mrp1 is unlikely to explain the
stimulated GSH ef 1047298ux Furthermore the 1047297nding that removal
of formaldehyde instantly decelerates the stimulated GSH
export (Tulpule and Dringen 2011 Tulpule et al 2012
2013) indicates that the mechanism responsible for formal-
dehyde-accelerated GSH export is quickly reversibleAssuming that cellular GSH is the transported Mrp1
substrate (Fig 2a) formaldehyde could stimulate GSH
export by a reversible covalent activation of this transporter
Alternatively a formaldehyde-induced recruitment of intra-
cellular Mrp1 molecules into the cell membrane could
explain the accelerated GSH export Such a reversible
translocation of Mrp1 from the Golgi to the cell surface
has been reported for cultured astrocytes treated with
bilirubin (Gennuso et al 2004)
Mrp1 ef 1047297ciently exports GSH conjugates (Keppler 2011
Yin and Zhang 2011) As the formaldehyde metabolism in
neural cells involves the generation of the GSH conjugatesS-hydroxymethyl GSH and S-formyl GSH (Fig 1) these
conjugates could also serve as substrates of Mrp1 (Fig 2b)
Since both conjugates are known to be labile (Ahmed and
Ahmed 1978 Uotila 1981) they are likely to disintegrate
into GSH and formaldehyde or formate immediately after
being exported
Direct experimental evidence that discriminates between
the potential two mechanisms (Fig 2) that may be involved
in the formaldehyde-induced accelerated GSH export via
Mrp1 is missing so far However determination of the
kinetic parameters for the GSH export from astrocytes
revealed that the K M-values of the basal as well as the
formaldehyde-accelerated GSH export from astrocytes are
identical (about 100 nmolmg or 25 mM) but that the
V max-value for the stimulated GSH export is eightfold higher
than that for the basal GSH export (Tulpule et al 2012)
These data suggest that at least for formaldehyde-treated
astrocytes GSH rather than a GSH conjugate is exported via
Mrp1 since the K M-values of Mrp1 for its substrate GSH are
normally higher than 5 mM while that for GSH conjugates
are below 1 mM (Burg et al 2002 Cole and Deeley 2006
Deeley and Cole 2006)
Application of formaldehyde does not deprive the cells
completely of their GSH and about 5 residual GSH still
remains within neural cells (Tulpule and Dringen 2011Tulpule et al 2012 2013) In cultured astrocytes this low
cellular GSH content represents a residual GSH concentra-
tion of about 04 mM (Dringen and Hamprecht 1998) which
will be suf 1047297cient to drive ADH3-catalyzed GSH-dependent
formaldehyde oxidation since the K M-value of ADH3 for
S-hydroxymethyl GSH is less than 10 lM (Casanova-
Schmitz et al 1984 Heck et al 1990) and this reaction
(a) (b)
Fig 2 Potential mechanisms involved in
formaldehyde-stimulated glutathione (GSH)
export from brain cells (a) Formaldehyde
directlystimulatesMrp1-mediatedGSH export
(b) The GSH conjugates S-hydroxymethyl
GSH andor S-formyl GSH which are
intermediates of cellular formaldehyde
metabolism are exported by Mrp1 The
labile conjugates immediately disintegrate
after export to generate GSH
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involves recycling of GSH (Fig 1) Thus the stimulated
GSH export is unlikely to compromise GSH-dependent
formaldehyde oxidation
Evidence for the role of formaldehyde in pathology
In healthy individuals the formaldehyde concentration in the
blood has been reported to be around 01 mM (Heck and
Casanova 2004) while that in the brain is about 02 mM
(hippocampus) and 04 mM (cortex) (Tong et al 2013a)
These levels of formaldehyde represent the normal phy-
siological balance between formaldehyde-generating and
formaldehyde-disposing processes However an increased
activity of formaldehyde-generating enzymes or an acute
exposure to high amounts of exogenous formaldehyde
without a concurrent elevation in the capacity to clear
formaldehyde will raise formaldehyde level in the body and
will lead to formaldehyde stress (He et al 2010) Indeed an
increased expressionactivity of the formaldehyde-generating
enzymes VAP1SSAO LSD1 and JHDM has been reported
for various diseases (Table 3) While a broad spectrum of
pathological conditions are associated with elevated levels of
VAP1SSAO an increase in the expression of the histone
demethylases has especially been observed in different types
of cancer (Table 3) The elevated expression of formalde-
hyde-generating enzymes is accompanied by increased
formaldehyde levels in diabetic rats (Tong et al 2013a) in
cancer tissue (Tong et al 2010) and in some human cancer
cell lines (Kato et al 2001 Tong et al 2010)
Increased expression of formaldehyde-generating enzymes
(Table 3) as well as elevated formaldehyde levels have also
been reported in brains of patients suffering from neurode-
generative diseases like Alzheimer rsquos disease (AD) or multi-
ple sclerosis (MS) (Khokhlov et al 1989 cited in Miao andHe 2012 Tong et al 2011 2013a) Some hypotheses have
been postulated that link the increase in formaldehyde level
to neuropathology For example some human subjects who
suffered from methanol poisoning developed symptoms of
MS which has been discussed to be an effect of methanol
oxidation to formaldehyde and the subsequent modi1047297cation
of proteins resulting in an immune reaction (Schwyzer and
Henzi 1983 Henzi 1984) Along that line it was discussed
that formaldehyde methylates proteins like tau (in AD) or
myelin basic protein (in MS) which in turn elicits an immune
response by the body that is characteristic for these diseases
(Monte 2010 Lu et al 2013) Also inhibition of SSAO in a
murine model of MS has been shown to reduce the incidence
and severity of this disease (Wang et al 2006) which could
at least partly be the consequence of a lowered formaldehyde
generation Moreover formaldehyde exposure has been
implicated to be a risk factor for the development of
amyotrophic lateral sclerosis (Weisskopf et al 2009) a
disease that is characterized by degeneration of motor
neurons (Kiernan et al 2011)
Formaldehyde-induced alterations in neuralmetabolism as potential contributors toneurodegeneration
Figure 3 summarizes the current knowledge on formalde-
hyde metabolism and on formaldehyde-induced alterations in
the glucose and GSH metabolism of neural cells The
potential of cultured brain cells to ef 1047297ciently metabolize
formaldehyde suggests that also the cells in brain deal quite
well with the moderate amounts of formaldehyde that are
generated under physiological conditions Similar to liver
cells brain cells are likely to use both cytosolic and
mitochondrial pathways for formaldehyde oxidation to
formate and further to carbon dioxide (Figs 1 and 3)
Cultured brain cells ef 1047297ciently produce and export glyco-
lytically generated lactate and also release GSH into the
medium although the basal rates of glycolysis and GSH
export differ between different types of neural cells (Tulpule
and Dringen 2011 2012 Tulpule et al 2012 2013) These
pathways are not affected by low concentrations of formal-
dehyde but as soon as formaldehyde levels are increased in
pathological conditions an accelerated generation of formate
is likely to stimulate glycolytic 1047298ux by inhibition of the
mitochondrial respiration (Fig 3) In addition an excess of
formaldehyde deprives brain cells of GSH by stimulating
Mrp1-mediated GSH export (Fig 3) Although caution should
be exercised while extrapolating in vitro data to the situation
in the brain a speculation on potential consequences of
Table 3 Elevation in expression or activity of formaldehyde-generat-
ing enzymes in human diseases
Enzyme Disease References
SSAOVAP1 Alzheimer rsquos disease Ferrer et al (2002) del Mar
Hernandez et al (2005)
Unzeta et al (2007)
Multiple sclerosis Airas et al (2006)
Heart disease Boomsma et al (2000 2005)
Diabetes mellitus
and diabetic
complications
Meszaros et al (1999)
Gr euroonvall-Nordquist
et al (2001) Karadi et al(2002) Boomsma et al
(2005) Obata (2006)
Chronic liver disease Kurkijarvi et al (2000)
LSD1JHDM Sarcoma Schildhaus et al (2011)
Bennani-Baiti et al (2012)
Peripheral nerve
sheath tumor
Schildhaus et al (2011)
Neuroblastoma Schulte et al (2009)
Bladder cancer Hayami et al (2010 2011)
Breast cancer Lim et al (2010)
Prost ate cancer Kahl et al (2006) Xiang
et al (2007)
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elevated formaldehyde levels in brain on the cellular metab-
olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of
cultured brain cells (01 ndash 1 mM) are in the concentration
range reported for the normal brain (02 ndash 04 mM) Thus mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig 4 Astrocytes and neurons in brain are likely to
ef 1047297ciently metabolize an excess of formaldehyde as also
reported for brain homogenates (Iborra et al 1992) Subse-
quently the formate generated from formaldehyde is either
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain
cells to at least transiently meet their energy demand
However prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al 2007) Besides this impairment of energy
metabolism formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003 Rose 2010) which would subsequently
induce astrocytic swelling impairment of neuronal signal
Fig 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the
generated formate is exported while a fraction is further oxidized to
carbon dioxide Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites
Fig 4 Potential consequences of an
excess of formaldehyde in brain Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed
indirect consequences (dark gray squares)
that 1047297nally lead to the adverse effects
reported for formaldehyde exposure
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
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Conflict of interest
The authors have no con1047298ict of interest to declare
References
Ahmed A E and Ahmed M W (1978) Metabolism of dihalomethanes
to formaldehyde and inorganic halide II Studies on the mechanism
of the reaction Biochem Pharmacol 27 2021 ndash 2025
Airas L Mikkola J Vainio J M Elovaara I and Smith D J (2006)
Elevated serum soluble vascular adhesion protein-1 (VAP-1) in
patients with active relapsing remitting multiple sclerosis
J Neuroimmunol 177 132 ndash 135
Alnouti Y and Klaassen C D (2008) Tissue distribution ontogeny and
regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by
prototypical microsomal enzyme inducers in mice Toxicol Sci
101 51 ndash 64
Anthony T E and Heintz N (2007) The folate metabolic enzyme
ALDH1L1 is restricted to the midline of the early CNS suggesting
a role in humanneural tubedefects J Comp Neurol 500 368 ndash 383Aslan H Songur A Tunc A T Ozen O A Bas O Yagmurca M
Turgut M Sarsilmaz M and Kaplan S (2006) Effects of
formaldehyde exposure on granule cell number and volume of
dentate gyrus a histopathological and stereological study Brain
Res 1122 191 ndash 200
Belkacemi A and Ramassamy C (2012) Time sequence of oxidative
stress in the brain from transgenic mouse models of Alzheimer rsquos
disease related to the amyloid-b cascade Free Radic Biol Med
52 593 ndash 600
Bennani-Baiti I M Machado I Llombart-Bosch A and Kovar H
(2012) Lysine-speci1047297c demethylase 1 (LSD1KDM1AAOF2
BHC110) is expressed and is an epigenetic drug target in
chondrosarcoma Ewingrsquos sarcoma osteosarcoma and
rhabdomyosarcoma Hum Pathol 43 1300 ndash 1307
Berkich D A Ola M S Cole J Sweatt A J Hutson S M andLaNoue K F (2007) Mitochondrial transport proteins of the brain
J Neurosci Res 85 3367 ndash 3377
Bola~nos J P Almeida A and Moncada S (2010) Glycolysis a
bioenergetic or a survival pathway Trends Biochem Sci 35 145 ndash
149
Boomsma F de Kam P J Tjeerdsma G van den Meiracker A H and
van Veldhuisen D J (2000) Plasma semicarbazide-sensitive amine
oxidase (SSAO) is an independent prognostic marker for mortality
in chronic heart failure Eur Heart J 21 1859 ndash 1863
Boomsma F Hut H Bagghoe U van der Houwen A and van den
Meiracker A (2005) Semicarbazide-sensitive amine oxidase
(SSAO) from cell to circulation Med Sci Monit 11 RA122 ndash
RA126
Boumezbeur F Mason G F de Graaf R A Behar K L Cline G W
Shulman G I Rothman D L and Petersen K F (2010) Alteredbrain mitochondrial metabolism in healthy aging as assessed by
in vivo magnetic resonance spectroscopy J Cereb Blood Flow
Metab 30 211 ndash 221
Burg D Wielinga P Zelcer N Saeki T Mulder G J and Borst P
(2002) Inhibition of the multidrug resistance protein 1 (MRP1) by
peptidomimetic glutathione-conjugate analogs Mol Pharmacol
62 1160 ndash 1166
Cahoy J D Emery B Kaushal A et al (2008) A transcriptome
database for astrocytes neurons and oligodendrocytes a new
resource for understanding brain development and function
J Neurosci 28 264 ndash 278
Casanova-Schmitz M David R M and Heck H D (1984) Oxidation of
formaldehyde and acetaldehyde by NAD+-dependent dehydrogenases
in rat nasal mucosal homogenates Biochem Pharmacol 33 1137 ndash
1142
Cheng X and Zhang X (2007) Structural dynamics of protein lysine
methylation and demethylation Mutat Res 618 102 ndash 115
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Cole S P C and Deeley R G (2006) Transport of glutathione and
glutathione conjugates by MRP1 Trends Pharmacol Sci 27 438 ndash
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Cook R J Champion K M and Giometti C S (2001) Methanol
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transporters in astrocytes and neurons observed in different
mouse brain cortical cell cultures J Neurosci Res 73 141 ndash 155
Deeley R G and Cole S P (2006) Substrate recognition and transport by multidrug resistance protein 1 (ABCC1) FEBS Lett 580 1103 ndash
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Dhareshwar S S and Stella V J (2008) Your prodrug releases
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Dicker E and Cederbaum A I (1984) Inhibition of the oxidation of
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Dringen R Kranich O and Hamprecht B (1997) The c-glutamyl
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Dringen R Hoepken H H Minich T and Ruedig C (2007) Pentosephosphate pathway and NADPH metabolism in Handbook of
Neurochemistry and Molecular Neurobiology (Dienel G and
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Fernandez-Fernandez S Almeida A and Bola~nos J P (2012)
Antioxidant and bioenergetic coupling between neurons and
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Ferrer I Lizcano J M Hernandez M and Unzeta M (2002)
Overexpression of semicarbazide sensitive amine oxidase in the
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Forneris F Battaglioli E Mattevi A and Binda C (2009) New roles of
1047298avoproteins in molecular cell biology histone demethylase LSD1
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C1-tetrahydrofolate synthase in fetal Down syndrome brain
J Neural Transm Suppl 67 85 ndash 93
Franks S J (2005) A mathematical model for the absorption and
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Friedenson B (2011) A common environmental carcinogen unduly
affects carriers of cancer mutations carriers of genetic mutations in
a speci1047297c protective response are more susceptible to an
environmental carcinogen Med Hypotheses 77 791 ndash 797
Fukuda T Tokunaga A Sakamoto R and Yoshida N (2011) Fbxl10
Kdm2b de1047297ciency accelerates neural progenitor cell death and
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16 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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Distribution of class I III and IV alcohol dehydrogenase mRNAs
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Gr euroonvall-Nordquist J L Backlund L B Garpenstrand H Ekblom J
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Hayami S Kelly J D Cho H S et al (2011) Overexpression of LSD1
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He R Lu J and Miao J (2010) Formaldehyde stress Sci China LifeSci 53 1399 ndash 1404
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Janaky R Cruz-Aguado R Oja S S and Shaw C A (2007)
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Karadi I Meszaros Z Csanyi A Szombathy T Hosszufalusi N
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Excessive S-adenosyl-L-methionine-dependent methylation
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Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
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Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
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Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
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Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
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Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
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Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
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Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
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Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
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Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
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cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
Neurochem Int 61 1302 ndash 1313
Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
metabolism and formaldehyde-induced stimulation of lactate
production and glutathione export in cultured neurons
J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
performance study Erciyes Med J 30 211 ndash 217
Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74
Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
vasculature pathological synergy of Alzheimer rsquos disease and
diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
(1997) Mitochondria-mediated cell injury Symposium overview
Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
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7212019 Journal of Neurochemistry
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Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
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doses of formaldehyde does not severely increase the
formaldehyde level in blood (Heck et al 1985 Franks
2005) This is expected as the formaldehyde-oxidizing
enzymes ADH3 and aldehyde dehydrogenase (ALDH) 2
(Fig 1) are ubiquitously expressed in all tissues (Nishimuraand Naito 2006 Alnouti and Klaassen 2008) and will
quickly clear a low excess of environmentally derived
formaldehyde However exposure to high concentrations of
exogenous formaldehyde that exceeds the peripheral form-
aldehyde oxidation capacity will elevate the normal tolerable
concentration of formaldehyde in the blood and could lead
to neural damage Indeed exposure to exogenous formal-
dehyde has been reported to cause neurotoxicity in humans
and animals and the extent of damage depends on the dose
of formaldehyde and the duration of the exposure (Kilburn
et al 1985a b Songur et al 2008 2010) Especially
individuals who carry functional polymorphisms in the
genes encoding for formaldehyde-metabolizing enzymes
ADH3 or ALDH2 which are discussed to be associated with
reduced formaldehyde-oxidizing capacity (Hedberg et al
2001 Wang et al 2002) may be more vulnerable to
neural damage by endogenously generated or environmental
formaldehyde
Metabolism of formaldehyde
Despite of the multiple endogenous and exogenous sources
of formaldehyde a low physiological level of formaldehyde
in body 1047298uids and tissue is maintained by the continuous
action of cellular formaldehyde-metabolizing enzymes(Fig 1) ADH1 is considered to play a negligible role in
formaldehyde reduction to methanol because of its very high
KM-value for formaldehyde (about 30 mM) (Skrzydlewska
2003) The formaldehyde oxidation product formate is
generated by two independent pathways that are mediated
by either the mitochondrial ALDH2 or the cytosolic ADH3
(Teng et al 2001 Friedenson 2011 MacAllister et al
2011) ADH3 also known as glutathione (GSH)-dependent
formaldehyde dehydrogenase oxidizes formaldehyde to
formate in a two-step process (Harris et al 2003 Staab
et al 2009 Thompson et al 2010 MacAllister et al 2011)
In the 1047297rst step GSH reacts with formaldehyde in an
enzyme-independent manner to form S-hydroxymethyl GSH
that is subsequently used as ADH3 substrate to generate S-
formyl GSH (Harris et al 2003 Staab et al 2009 Thomp-
son et al 2010 MacAllister et al 2011) The conjugate S-
formyl GSH is hydrolyzed by a thiolase to generate formate
and GSH (Teng et al 2001 Harris et al 2003 MacAllister
et al 2011) Unlike ADH3 the reaction catalyzed by
ALDH2 is a single-step GSH-independent process (Teng
et al 2001 MacAllister et al 2011) Since ADH3 has a
very low KM-value for S-hydroxymethyl GSH (less than
10 lM) compared to that of ALDH2 for formaldehyde (02 ndash
05 mM) (Casanova-Schmitz et al 1984 Heck et al 1990)
ADH3 is likely to be especially important for the oxidation
of low concentrations of formaldehyde
The formate generated by formaldehyde oxidation can
undergo further oxidization to carbon dioxide in a metabolic
pathway involving tetrahydrofolate (THF) wherein formateis 1047297rst converted to 10-formyl THF (Fig 1) in an ATP-
dependent reaction (Skrzydlewska 2003 Krupenko 2009
Krupenko et al 2010) This reaction is catalyzed either by
the cytosolic methylene tetrahydrofolate dehydrogenase
(MTHFD) 1 or by its mitochondrial isoform MTHFD1L
(Tibbetts and Appling 2010) 10-formyl THF is subsequently
oxidized by the cytosolic 10-formyl THF dehydrogenase
also known as ALDH1L1 or its mitochondrial isoform
ALDH1L2 to carbon dioxide Both enzymes use NADP+ as a
co-factor and regenerate THF (Skrzydlewska 2003 Kru-
penko 2009 Krupenko et al 2010) Although formate
oxidation takes place predominantly by the THF-dependent
pathway catalase-mediated oxidation of formate has also
been reported (Cook et al 2001 Skrzydlewska 2003)
Formaldehyde metabolism (Fig 1) is best studied for the
liver (Skrzydlewska 2003 Tibbetts and Appling 2010) but it
is very likely that other organs including the brain will also
use the enzymatic pathways that are well known for
formaldehyde metabolism in liver In brain at least all the
enzymes required for complete formaldehyde oxidation are
expressed (Table 1)
Differences in the rate of formaldehyde metabolism have
been described between species for the formaldehyde
metabolism For example formate is metabolized at a slower
rate in the liver of monkeys and humans compared to ratspartly because rats have a higher hepatic THF content
(Tephly 1991 Skrzydlewska 2003) Also species-speci1047297c
differences in the kinetic parameters of the enzymes involved
in formaldehyde metabolism may contribute to the different
rates of formaldehyde oxidation observed and subsequently
may determine the consequences of an exposure to formal-
dehyde andor it metabolites
Generation and oxidation of formaldehydein brain cells
Several reports have demonstrated that the enzymes required
to produce or metabolize formaldehyde are expressed in the
brain on the mRNA or protein level (Table 1) Of these
enzymes only the expression of ADH1 in the brain has been
controversially discussed since this dehydrogenase was not
detected in brain by some investigators (Julia et al 1987
Galter et al 2003) Despite the presence of ADH1 mRNA in
cultured neural cells methanol generation was not found for
formaldehyde-exposed cultured brain cells (Tulpule and
Dringen 2012 Tulpule et al 2013) suggesting that oxida-
tion to formate is the preferred pathway of formaldehyde
metabolism in brain cells Cultured astrocytes and neurons
contain the mRNAs for SSAO and LSD1 as well as for the
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enzymes involved in formaldehyde metabolism (Tulpule and
Dringen 2012 Tulpule et al 2013) These studies indicate
that formaldehyde may be produced locally in the brain and
that among the different types of brain cells at least astrocytes
and neurons have the potential to generate and oxidize
formaldehyde
Acute formaldehyde exposure in concentrations of up to
1 mM for up to 3 h does not cause severe toxicity in cultured
astrocytes or neurons (Song et al 2010 Tulpule and Dringen2011 2012 Tulpule et al 2013) A rapid metabolism of
cellular formaldehyde may contribute to the resistance of
cultured brain cells to formaldehyde toxicity since formal-
dehyde has been reported to be more cytotoxic than its
metabolites methanol and formate (Oyama et al 2002 Lee
et al 2008) Both cultured astrocytes and neurons clear
exogenously applied formaldehyde with a similar rate of
around 02 lmol(h 9 mg) (Tulpule and Dringen 2012
Tulpule et al 2013) which is about 20 of the formaldehyde
oxidation rate reported for liver cells (Dicker and Cederbaum
1984) The K M-value for formaldehyde clearance by cultured
astrocytes is around 019 mM suggesting that both the
cytosolic ADH3 and mitochondrial ALDH2 could contribute
to formaldehyde oxidation (Tulpule and Dringen 2012)
Although cultured astrocytes and neurons have compara-
ble rates of formaldehyde clearance the metabolic fate of the
disposed formaldehyde differs between these two types of
neural cells Although astrocytes convert the majority
(gt 90) of formaldehyde to formate that is subsequently
exported from the cells (Tulpule and Dringen 2012) only
about 25 of the formaldehyde cleared by cultured neurons
is detected as extracellular formate (Tulpule et al 2013) The
underlying reason for this difference might be a poor export
of formate from cultured neurons andor a higher capacity of
these cells to further oxidize formate to carbon dioxide
(Fig 1) Although the putative formate exporters GABA-
gated channels (Mason et al 1990) and monocarboxylate
transporter (MCT) 1 (Moschen et al 2012) are expressed in
both astrocytes and neurons (Debernardi et al 2003 Olsen
and Sieghart 2009 Lee et al 2011 Velez-Fort et al 2011)
the expression level of MCT1 in neurons has been reported
to be very low (Debernardi et al 2003) However if poor
export of formate would be the only reason behind the lower extracellular accumulation of this metabolite in cultured
neurons these cells should accumulate large amounts of
formaldehyde-derived formate which is not the case (Tulp-
ule et al 2013) Thus the lower extracellular accumulation
of formaldehyde-derived formate in cultured neurons com-
pared to cultured astrocytes is likely to be predominantly
caused by oxidation of formaldehyde-derived cellular
formate to carbon dioxide The enzymes involved in the
oxidation of 10-formyl THF require NADP+ as electron
acceptor (Krupenko 2009 Krupenko et al 2010) and the
availability of NADP+ in cytosol and mitochondria depends
on the pathways involved in NADPH consumption and
NADPH regeneration As such pathways differ between
astrocytes and neurons (Dringen et al 2007) the NADP+
availability could also contribute to the differences observed
in formate release from astrocytes and neurons that were
exposed to formaldehyde (Tulpule and Dringen 2012
Tulpule et al 2013)
Alterations of the metabolism of braincells upon exposure to formaldehyde
A large number of adverse consequences have been reported
for an exposure of brain cells to formaldehyde in vivo and
Table 1 Formaldehyde-producing and formaldehyde-metabolizing enzymes in the brain
Enzymes
Species
Rat Mouse Human
Formaldehyde generation
ADH1 Martinez et al (2001)
Catalase Zimatkin and Lindros (1996) Schad et al (2003) Meinerz et al (2013) van Horssen et al (2008)
SSAOVAP1 Obata and Yamanaka (2000) Ferrer et al (2002) Unzeta et al (2007)
Valente et al (2012)
LSD1 Zibetti et al (2010) Zhang et al (2010) Zibetti et al (2010)
JHDM Wolf et al (2007) Fukuda et al (2011) Wolf et al (2007)
Formaldehyde oxidation
ADH3 Julia et al (1987) Iborra et al (1992)
Galter et al (2003)
Galter et al (2003) Galter et al (2003)
ALDH2 Guo et al (2013) Alnouti and Klaassen (2008) Stewart et al (1996)
Formate oxidation
MTHFD1 Thigpen et al (1990) MacFarlane et al (2009) Fountoulakis et al (2003)
MTHFD1L Prasannan et al (2003)
ALDH1L1 Neymeyer et al (1997) Anthony and Heintz (2007) Cahoy et al (2008) Oldham et al (2008)
ALDH1L2 Krupenko et al (2010)
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in vitro (Table 2) Recently it was demonstrated that
formaldehyde in the concentration range between 01 mM
and 1 mM strongly affects basal metabolic properties of
cultured astrocytes and neurons that is formaldehyde
stimulates glycolytic 1047298ux and the export of the antioxidative
tripeptide GSH from brain cells
Formaldehyde-stimulated glycolysisAstrocytes are more glycolytic than neurons (Bola~nos et al
2010) a feature which has been attributed to expression of
the glycolysis-promoting enzyme PFKFB3 in astrocytes
(Herrero-Mendez et al 2009) an inhibited pyruvate dehy-
drogenase complex (Halim et al 2010) and a low rate of
NADH shuttling into mitochondria in astrocytes (Berkich
et al 2007 Neves et al 2012) Despite the differences in
basal rates of glucose consumption and lactate release in
cultured astrocytes and neurons application of formaldehyde
signi1047297cantly increases these rates in both types of brain cells
(Tulpule and Dringen 2012 Tulpule et al 2013) However
the extent of stimulation of glycolytic 1047298ux in formaldehyde-
exposed cells compared to the basal condition differs
between the culture types investigated For example at a
formaldehyde concentration of 05 mM the lactate release
and glucose consumption rates were doubled in cultured
neurons (Tulpule et al 2013) while this concentration of
formaldehyde did not affect glycolysis in cultured astrocytes
(Tulpule and Dringen 2012) Astrocytes had to be exposed to
1 mM formaldehyde to elevate glycolysis by 50 (Tulpule
and Dringen 2012)
The accelerated glycolysis in formaldehyde-exposed neu-
ral cells is likely to be caused by the formaldehyde-derived
formate which is known to inhibit mitochondrial cytochrome
c oxidase (Nicholls 1975 Wallace et al 1997) This view is
supported by the observation that incubation of astrocytes
with formaldehyde for 90 min is required for the accelerated
lactate release to persist even after removal of formaldehyde
(Tulpule and Dringen 2012) This long delay most likely
re1047298ects the slow mitochondrial accumulation of formalde-
hyde-derived formate to concentrations that are suf 1047297cient to
inactivate respiration as most of the formate is ef 1047297cientlyexported from astrocytes Moreover the persistent lactate
release of astrocytes exposed to formaldehyde was not
further enhanced by application of azide an inhibitor of
mitochondrial cytochrome c oxidase (Tulpule and Dringen
2012) Thus formaldehyde-derived formate is likely to
stimulate glycolytic 1047298ux as a consequence of an inhibited
respiration as also other inhibitors of respiratory chain
complexes stimulate glycolytic lactate production in cultured
astrocytes and neurons (Pauwels et al 1985 Scheiber and
Dringen 2011)
Formaldehyde-accelerated glutathione export
GSH is an important antioxidant (Lushchak 2012 Schmidt
and Dringen 2012 Lu 2013) that is also involved in the
formaldehyde oxidation catalyzed by ADH3 (Fig 1) Under
basal conditions cultured astrocytes and neurons as well as
cells of the oligodendroglial cell line OLN-93 export GSH
although with variable rates (Tulpule and Dringen 2011
Tulpule et al 2012 2013) Formaldehyde treatment stimu-
lated GSH export from all three types of cultured neural cells
without severely altering the ratio of GSH to glutathione
disul1047297de (GSSG) (Tulpule and Dringen 2011 Tulpule et al
2012 2013) This accelerated GSH export from formalde-
hyde-treated neural cells is mediated by multidrug resistance
Table 2 Consequences of a formaldehyde exposure of rodent brain cells in vivo and in vitro
References
In vivo
Decrease in the number of neuron Gurel et al (2005) Aslan et al (2006) Sarsilmaz et al (2007)Decreased level of GSH Lu et al (2008)
Lowered levels of superoxide dismutase and catalase Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in levels of nitric oxide malondialdehyde
and protein carbonyls
Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in apoptotic events Zararsiz et al (2006 2007)
De1047297cit in memory and learning Pitten et al (2000) Usanmaz et al (2002) Malek et al (2003)
Sorg et al (2004) Lu et al (2008) Turkoglu et al (2008)
Tong et al (2011 2013a b)
In vitro
Elevated glycolysis in neurons and astrocytes Tulpule and Dringen (2012) Tulpule et al (2013)
Mrp1-stimulated GSH export from neurons and astrocytes Tulpule and Dringen (2011) Tulpule et al (2013)
Decreased gl utamate uptake in cultured astrocytes Song et al (2010)
Lower expression of neuronal NMDA receptor subunits Tong et al (2013a)
The articles by Lu et al (2008) Usanmaz et al (2002) and Tong et al (2011) describe data that have been obtained on mice whereas all other
studies were performed on rats or rat brain cells
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
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7212019 Journal of Neurochemistry
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protein (Mrp) 1 (Tulpule and Dringen 2011 Tulpule et al
2012 2013) Mrp1 is a member of ATP-binding cassette
transporters and transports besides GSH a wide array of
substrates including GSSG and GSH conjugates (Keppler
2011 Yin and Zhang 2011) The potential of formaldehydeto accelerate GSH export differs between different brain cell
culture types For example exposure to 05 mM formalde-
hyde increased the respective GSH export rates of cultured
astrocytes neurons and OLN-93 cells by 10- 5- and 20-fold
respectively (Tulpule and Dringen 2011 Tulpule et al 2012
2013) However half-maximal cellular GSH depletions were
observed at similar incubation parameters for all types of
neural cells after incubation for 1 h with 03 mM formalde-
hyde (Tulpule and Dringen 2011 Tulpule et al 2012 2013)
Formaldehyde exposure does not impair the capacity of
neural cells to synthesize GSH At least formaldehyde-treated
neurons restored their cellular GSH levels after application of
amino acid precursors for GSH synthesis (Tulpule et al
2013)
The molecular mechanism involved in the formaldehyde-
accelerated Mrp1-mediated GSH export from neural cells is
not resolved so far Since the stimulation of GSH export is
observed within minutes after formaldehyde application
(Tulpule and Dringen 2011 Tulpule et al 2012 2013)
de novo synthesis of Mrp1 is unlikely to explain the
stimulated GSH ef 1047298ux Furthermore the 1047297nding that removal
of formaldehyde instantly decelerates the stimulated GSH
export (Tulpule and Dringen 2011 Tulpule et al 2012
2013) indicates that the mechanism responsible for formal-
dehyde-accelerated GSH export is quickly reversibleAssuming that cellular GSH is the transported Mrp1
substrate (Fig 2a) formaldehyde could stimulate GSH
export by a reversible covalent activation of this transporter
Alternatively a formaldehyde-induced recruitment of intra-
cellular Mrp1 molecules into the cell membrane could
explain the accelerated GSH export Such a reversible
translocation of Mrp1 from the Golgi to the cell surface
has been reported for cultured astrocytes treated with
bilirubin (Gennuso et al 2004)
Mrp1 ef 1047297ciently exports GSH conjugates (Keppler 2011
Yin and Zhang 2011) As the formaldehyde metabolism in
neural cells involves the generation of the GSH conjugatesS-hydroxymethyl GSH and S-formyl GSH (Fig 1) these
conjugates could also serve as substrates of Mrp1 (Fig 2b)
Since both conjugates are known to be labile (Ahmed and
Ahmed 1978 Uotila 1981) they are likely to disintegrate
into GSH and formaldehyde or formate immediately after
being exported
Direct experimental evidence that discriminates between
the potential two mechanisms (Fig 2) that may be involved
in the formaldehyde-induced accelerated GSH export via
Mrp1 is missing so far However determination of the
kinetic parameters for the GSH export from astrocytes
revealed that the K M-values of the basal as well as the
formaldehyde-accelerated GSH export from astrocytes are
identical (about 100 nmolmg or 25 mM) but that the
V max-value for the stimulated GSH export is eightfold higher
than that for the basal GSH export (Tulpule et al 2012)
These data suggest that at least for formaldehyde-treated
astrocytes GSH rather than a GSH conjugate is exported via
Mrp1 since the K M-values of Mrp1 for its substrate GSH are
normally higher than 5 mM while that for GSH conjugates
are below 1 mM (Burg et al 2002 Cole and Deeley 2006
Deeley and Cole 2006)
Application of formaldehyde does not deprive the cells
completely of their GSH and about 5 residual GSH still
remains within neural cells (Tulpule and Dringen 2011Tulpule et al 2012 2013) In cultured astrocytes this low
cellular GSH content represents a residual GSH concentra-
tion of about 04 mM (Dringen and Hamprecht 1998) which
will be suf 1047297cient to drive ADH3-catalyzed GSH-dependent
formaldehyde oxidation since the K M-value of ADH3 for
S-hydroxymethyl GSH is less than 10 lM (Casanova-
Schmitz et al 1984 Heck et al 1990) and this reaction
(a) (b)
Fig 2 Potential mechanisms involved in
formaldehyde-stimulated glutathione (GSH)
export from brain cells (a) Formaldehyde
directlystimulatesMrp1-mediatedGSH export
(b) The GSH conjugates S-hydroxymethyl
GSH andor S-formyl GSH which are
intermediates of cellular formaldehyde
metabolism are exported by Mrp1 The
labile conjugates immediately disintegrate
after export to generate GSH
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
12 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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involves recycling of GSH (Fig 1) Thus the stimulated
GSH export is unlikely to compromise GSH-dependent
formaldehyde oxidation
Evidence for the role of formaldehyde in pathology
In healthy individuals the formaldehyde concentration in the
blood has been reported to be around 01 mM (Heck and
Casanova 2004) while that in the brain is about 02 mM
(hippocampus) and 04 mM (cortex) (Tong et al 2013a)
These levels of formaldehyde represent the normal phy-
siological balance between formaldehyde-generating and
formaldehyde-disposing processes However an increased
activity of formaldehyde-generating enzymes or an acute
exposure to high amounts of exogenous formaldehyde
without a concurrent elevation in the capacity to clear
formaldehyde will raise formaldehyde level in the body and
will lead to formaldehyde stress (He et al 2010) Indeed an
increased expressionactivity of the formaldehyde-generating
enzymes VAP1SSAO LSD1 and JHDM has been reported
for various diseases (Table 3) While a broad spectrum of
pathological conditions are associated with elevated levels of
VAP1SSAO an increase in the expression of the histone
demethylases has especially been observed in different types
of cancer (Table 3) The elevated expression of formalde-
hyde-generating enzymes is accompanied by increased
formaldehyde levels in diabetic rats (Tong et al 2013a) in
cancer tissue (Tong et al 2010) and in some human cancer
cell lines (Kato et al 2001 Tong et al 2010)
Increased expression of formaldehyde-generating enzymes
(Table 3) as well as elevated formaldehyde levels have also
been reported in brains of patients suffering from neurode-
generative diseases like Alzheimer rsquos disease (AD) or multi-
ple sclerosis (MS) (Khokhlov et al 1989 cited in Miao andHe 2012 Tong et al 2011 2013a) Some hypotheses have
been postulated that link the increase in formaldehyde level
to neuropathology For example some human subjects who
suffered from methanol poisoning developed symptoms of
MS which has been discussed to be an effect of methanol
oxidation to formaldehyde and the subsequent modi1047297cation
of proteins resulting in an immune reaction (Schwyzer and
Henzi 1983 Henzi 1984) Along that line it was discussed
that formaldehyde methylates proteins like tau (in AD) or
myelin basic protein (in MS) which in turn elicits an immune
response by the body that is characteristic for these diseases
(Monte 2010 Lu et al 2013) Also inhibition of SSAO in a
murine model of MS has been shown to reduce the incidence
and severity of this disease (Wang et al 2006) which could
at least partly be the consequence of a lowered formaldehyde
generation Moreover formaldehyde exposure has been
implicated to be a risk factor for the development of
amyotrophic lateral sclerosis (Weisskopf et al 2009) a
disease that is characterized by degeneration of motor
neurons (Kiernan et al 2011)
Formaldehyde-induced alterations in neuralmetabolism as potential contributors toneurodegeneration
Figure 3 summarizes the current knowledge on formalde-
hyde metabolism and on formaldehyde-induced alterations in
the glucose and GSH metabolism of neural cells The
potential of cultured brain cells to ef 1047297ciently metabolize
formaldehyde suggests that also the cells in brain deal quite
well with the moderate amounts of formaldehyde that are
generated under physiological conditions Similar to liver
cells brain cells are likely to use both cytosolic and
mitochondrial pathways for formaldehyde oxidation to
formate and further to carbon dioxide (Figs 1 and 3)
Cultured brain cells ef 1047297ciently produce and export glyco-
lytically generated lactate and also release GSH into the
medium although the basal rates of glycolysis and GSH
export differ between different types of neural cells (Tulpule
and Dringen 2011 2012 Tulpule et al 2012 2013) These
pathways are not affected by low concentrations of formal-
dehyde but as soon as formaldehyde levels are increased in
pathological conditions an accelerated generation of formate
is likely to stimulate glycolytic 1047298ux by inhibition of the
mitochondrial respiration (Fig 3) In addition an excess of
formaldehyde deprives brain cells of GSH by stimulating
Mrp1-mediated GSH export (Fig 3) Although caution should
be exercised while extrapolating in vitro data to the situation
in the brain a speculation on potential consequences of
Table 3 Elevation in expression or activity of formaldehyde-generat-
ing enzymes in human diseases
Enzyme Disease References
SSAOVAP1 Alzheimer rsquos disease Ferrer et al (2002) del Mar
Hernandez et al (2005)
Unzeta et al (2007)
Multiple sclerosis Airas et al (2006)
Heart disease Boomsma et al (2000 2005)
Diabetes mellitus
and diabetic
complications
Meszaros et al (1999)
Gr euroonvall-Nordquist
et al (2001) Karadi et al(2002) Boomsma et al
(2005) Obata (2006)
Chronic liver disease Kurkijarvi et al (2000)
LSD1JHDM Sarcoma Schildhaus et al (2011)
Bennani-Baiti et al (2012)
Peripheral nerve
sheath tumor
Schildhaus et al (2011)
Neuroblastoma Schulte et al (2009)
Bladder cancer Hayami et al (2010 2011)
Breast cancer Lim et al (2010)
Prost ate cancer Kahl et al (2006) Xiang
et al (2007)
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
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elevated formaldehyde levels in brain on the cellular metab-
olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of
cultured brain cells (01 ndash 1 mM) are in the concentration
range reported for the normal brain (02 ndash 04 mM) Thus mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig 4 Astrocytes and neurons in brain are likely to
ef 1047297ciently metabolize an excess of formaldehyde as also
reported for brain homogenates (Iborra et al 1992) Subse-
quently the formate generated from formaldehyde is either
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain
cells to at least transiently meet their energy demand
However prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al 2007) Besides this impairment of energy
metabolism formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003 Rose 2010) which would subsequently
induce astrocytic swelling impairment of neuronal signal
Fig 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the
generated formate is exported while a fraction is further oxidized to
carbon dioxide Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites
Fig 4 Potential consequences of an
excess of formaldehyde in brain Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed
indirect consequences (dark gray squares)
that 1047297nally lead to the adverse effects
reported for formaldehyde exposure
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14 K Tulpule and R Dringen
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
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Conflict of interest
The authors have no con1047298ict of interest to declare
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of short chain fatty acid transport by members of the
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Mukherjee S and Manahan-Vaughan D (2013) Role of metabotropic
glutamate receptors in persistent forms of hippocampal plasticity
and learning Neuropharmacology 66 65 ndash 81
Nazarian A Hermannsson B J Muller J Zurakowski D and Snyder
B D (2009) Effects of tissue preservation on murine bone
mechanical properties J Biomech 42 82 ndash 86
Neves A Costalat R and Pellerin L (2012) Determinants of brain
cell metabolic phenotypes and energy substrate utilization unraveled
with a modeling approach PLoS Comput Biol 8 e1002686
Neymeyer V Tephly T R and Miller M W (1997) Folate and 10-
formyltetrahydrofolate dehydrogenase (FDH) expression in the
central nervous system of the mature rat Brain Res 766 195 ndash 204
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
18 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1315
Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase
Biochem Biophys Res Commun 67 610 ndash 616
Nishimura M and Naito S (2006) Tissue-speci1047297c mRNA expression
pro1047297les of human phase I metabolizing enzymes except for
cytochrome P450 and phase II metabolizing enzymes Drug
Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
(SSAO) activity a review Life Sci 79 417 ndash 422
Obata T and Yamanaka Y (2000) Evidence for existence of
immobilization stress-inducible semicarbazide-sensitive amine
oxidase inhibitor in rat brain cytosol Neurosci Lett 296 58 ndash 60
Oldham M C Konopka G Iwamoto K Langfelder P Kato T
Horvath S and Geschwind D (2008) Functional organization of
the transcriptome in the human brain Nat Neurosci 11 1271 ndash
1282
Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide
diversity of function and pharmacology Neuropharmacology 56
141 ndash 148
OrsquoSullivan J Unzeta M Healy J OrsquoSullivan M I Davey G and
Tipton K F (2004) Semicarbazide-sensitive amine oxidases
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formate on dissociated rat thymocytes a possibility of aspartame
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Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D
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using MR techniques J Neurol 258 2113 ndash 2127
Parnetti L Reboldi G P and Gallai V (2000) Cerebrospinal 1047298uid
pyruvate levels in Alzheimer rsquos disease and vascular dementia
Neurology 54 735 ndash 737
Pauwels P J Opperdoes F R and Trouet A (1985) Effects of
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Pitten F A Kramer A Herrmann K Breme I and Koch S (2000)
Formaldehyde neurotoxicity in animal experiments Pathol ResPract 196 193 ndash 198
Prasannan P Pike S Peng K Shane B and Appling D R (2003)
Human mitochondrial C1-tetrahydrofolate synthase gene structure
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glucose deprivation Brain Res 817 145 ndash 150
Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
high concentrations of extracellular reduced glutathione
Neuroscience 91 463 ndash 470
Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
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of resveratrol and derivatives Ann N Y Acad Sci 1215 103 ndash
108Rose C F (2010) Increase brain lactate in hepatic encephalopathy cause
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Ross J M Oberg J Brene S et al (2010) High brain lactate is a
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dehydrogenase AB ratio Proc Natl Acad Sci USA 107
20087 ndash 20092
Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
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Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
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Sasseville D (2004) Hypersensitivity to preservatives Dermatol Ther
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Schad A Fahimi H D Volkl A and Baumgart E (2003) Expression
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by catalyzed reporter deposition (ISH-CAR D) and
immunohistochemistry (IHC)immuno1047298uorescence (IF) J
Histochem Cytochem 51 751 ndash 760
Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux
in cultured astrocytes Neurochem Res 36 894 ndash 903
Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c
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synovial sarcomas rhabdomyosarcomas desmoplastic small round
cell tumors and malignant peripheral nerve sheath tumors Hum
Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
1029 ndash 1050 Neural Metabolism in vivo Springer New York
Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
neuroblastoma implications for therapy Cancer Res 69 2065 ndash
2071
Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
by 2-step demyelination Med Hypotheses 12 129 ndash 142
Skrzydlewska E (2003) Toxicological and metabolic consequences of
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Smith D J and Vainio P J (2007) Targeting vascular adhesion protein-
1 to treat autoimmune and in1047298ammatory diseases Ann N Y Acad
Sci 1110 382 ndash 388
Sohal R S and Orr W C (2012) The redox stress hypothesis of aging
Free Radic Biol Med 52 539 ndash 555
Song M S Baker G B Dursun S M and Todd K G (2010) The
antidepressant phenelzine protects neurons and astrocytes
against formaldehyde-induced toxicity J Neurochem 1141405 ndash 1413
Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
Ilhan N (2008) The effects of inhaled formaldehyde on oxidant and
antioxidant systems of rat cerebellum during the postnatal
development process Toxicol Mech Methods 18 569 ndash 574
Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
formaldehyde on the nervous system Rev Environ Contam
Toxicol 203 105 ndash 118
Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
formaldehyde exposure produces enhanced fear conditioning to
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Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
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Interact 178 29 ndash 35
Staub F Peters J Kempski O Schneider G H Schurer Land Baethmann A (1993) Swelling of glial cells in lactacidosis
and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash
74
Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
less support implications for Alzheimer rsquos disease Neurobiol
Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
P Cuenod M and Do K Q (2010) Redox dysregulation affects
the ventral but not dorsal hippocampus impairment of
parvalbumin neurons gamma oscillations and related behaviors
J Neurosci 30 2547 ndash 2558
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Formaldehyde in brain 19
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1415
Stewart M J Malek K and Crabb D W (1996) Distribution of
messenger RNAs for aldehyde dehydrogenase 1 aldehyde
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Sullivan P G and Brown M R (2005) Mitochondrial aging and
dysfunction in Alzheimer rsquos disease Prog Neuropsychopharmacol
Biol Psychiatry 29 407 ndash 410
Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
Magistretti P J and Alberini C M (2011) Astrocyte-neuron
lactate transport is required for long-term memory formation Cell
144 810 ndash 823
Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
and health effects Environ Int 35 1210 ndash 1224
Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
neurotoxicity to PC12 cells involving inhibition of paraoxonase-1
expression and activity Clin Exp Pharmacol Physiol 38 208 ndash
214
Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
1041
Thigpen A E West M G and Appling D R (1990) Rat C1-
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Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
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1 ndash 3
Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev
Nutr 30 57 ndash 81
Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
formaldehyde and acidic microenvironment synergistically induce
bone cancer pain PLoS ONE 5 e10234
Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
inversely correlated to mini mental state examination scores in
senile dementia Neurobiol Aging 32 31 ndash 41
Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
R (2013a) Accumulated hippocampal formaldehyde induces age-
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Tong Z Han C Luo W et al (2013b) Aging-associated excess
formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635
Tulpule K and Dringen R (2012) Formate generated by cellular
oxidation of formaldehyde accelerates the glycolytic 1047298ux in
cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
Neurochem Int 61 1302 ndash 1313
Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
metabolism and formaldehyde-induced stimulation of lactate
production and glutathione export in cultured neurons
J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
performance study Erciyes Med J 30 211 ndash 217
Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74
Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
vasculature pathological synergy of Alzheimer rsquos disease and
diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
(1997) Mitochondria-mediated cell injury Symposium overview
Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
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enzymes involved in formaldehyde metabolism (Tulpule and
Dringen 2012 Tulpule et al 2013) These studies indicate
that formaldehyde may be produced locally in the brain and
that among the different types of brain cells at least astrocytes
and neurons have the potential to generate and oxidize
formaldehyde
Acute formaldehyde exposure in concentrations of up to
1 mM for up to 3 h does not cause severe toxicity in cultured
astrocytes or neurons (Song et al 2010 Tulpule and Dringen2011 2012 Tulpule et al 2013) A rapid metabolism of
cellular formaldehyde may contribute to the resistance of
cultured brain cells to formaldehyde toxicity since formal-
dehyde has been reported to be more cytotoxic than its
metabolites methanol and formate (Oyama et al 2002 Lee
et al 2008) Both cultured astrocytes and neurons clear
exogenously applied formaldehyde with a similar rate of
around 02 lmol(h 9 mg) (Tulpule and Dringen 2012
Tulpule et al 2013) which is about 20 of the formaldehyde
oxidation rate reported for liver cells (Dicker and Cederbaum
1984) The K M-value for formaldehyde clearance by cultured
astrocytes is around 019 mM suggesting that both the
cytosolic ADH3 and mitochondrial ALDH2 could contribute
to formaldehyde oxidation (Tulpule and Dringen 2012)
Although cultured astrocytes and neurons have compara-
ble rates of formaldehyde clearance the metabolic fate of the
disposed formaldehyde differs between these two types of
neural cells Although astrocytes convert the majority
(gt 90) of formaldehyde to formate that is subsequently
exported from the cells (Tulpule and Dringen 2012) only
about 25 of the formaldehyde cleared by cultured neurons
is detected as extracellular formate (Tulpule et al 2013) The
underlying reason for this difference might be a poor export
of formate from cultured neurons andor a higher capacity of
these cells to further oxidize formate to carbon dioxide
(Fig 1) Although the putative formate exporters GABA-
gated channels (Mason et al 1990) and monocarboxylate
transporter (MCT) 1 (Moschen et al 2012) are expressed in
both astrocytes and neurons (Debernardi et al 2003 Olsen
and Sieghart 2009 Lee et al 2011 Velez-Fort et al 2011)
the expression level of MCT1 in neurons has been reported
to be very low (Debernardi et al 2003) However if poor
export of formate would be the only reason behind the lower extracellular accumulation of this metabolite in cultured
neurons these cells should accumulate large amounts of
formaldehyde-derived formate which is not the case (Tulp-
ule et al 2013) Thus the lower extracellular accumulation
of formaldehyde-derived formate in cultured neurons com-
pared to cultured astrocytes is likely to be predominantly
caused by oxidation of formaldehyde-derived cellular
formate to carbon dioxide The enzymes involved in the
oxidation of 10-formyl THF require NADP+ as electron
acceptor (Krupenko 2009 Krupenko et al 2010) and the
availability of NADP+ in cytosol and mitochondria depends
on the pathways involved in NADPH consumption and
NADPH regeneration As such pathways differ between
astrocytes and neurons (Dringen et al 2007) the NADP+
availability could also contribute to the differences observed
in formate release from astrocytes and neurons that were
exposed to formaldehyde (Tulpule and Dringen 2012
Tulpule et al 2013)
Alterations of the metabolism of braincells upon exposure to formaldehyde
A large number of adverse consequences have been reported
for an exposure of brain cells to formaldehyde in vivo and
Table 1 Formaldehyde-producing and formaldehyde-metabolizing enzymes in the brain
Enzymes
Species
Rat Mouse Human
Formaldehyde generation
ADH1 Martinez et al (2001)
Catalase Zimatkin and Lindros (1996) Schad et al (2003) Meinerz et al (2013) van Horssen et al (2008)
SSAOVAP1 Obata and Yamanaka (2000) Ferrer et al (2002) Unzeta et al (2007)
Valente et al (2012)
LSD1 Zibetti et al (2010) Zhang et al (2010) Zibetti et al (2010)
JHDM Wolf et al (2007) Fukuda et al (2011) Wolf et al (2007)
Formaldehyde oxidation
ADH3 Julia et al (1987) Iborra et al (1992)
Galter et al (2003)
Galter et al (2003) Galter et al (2003)
ALDH2 Guo et al (2013) Alnouti and Klaassen (2008) Stewart et al (1996)
Formate oxidation
MTHFD1 Thigpen et al (1990) MacFarlane et al (2009) Fountoulakis et al (2003)
MTHFD1L Prasannan et al (2003)
ALDH1L1 Neymeyer et al (1997) Anthony and Heintz (2007) Cahoy et al (2008) Oldham et al (2008)
ALDH1L2 Krupenko et al (2010)
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
10 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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in vitro (Table 2) Recently it was demonstrated that
formaldehyde in the concentration range between 01 mM
and 1 mM strongly affects basal metabolic properties of
cultured astrocytes and neurons that is formaldehyde
stimulates glycolytic 1047298ux and the export of the antioxidative
tripeptide GSH from brain cells
Formaldehyde-stimulated glycolysisAstrocytes are more glycolytic than neurons (Bola~nos et al
2010) a feature which has been attributed to expression of
the glycolysis-promoting enzyme PFKFB3 in astrocytes
(Herrero-Mendez et al 2009) an inhibited pyruvate dehy-
drogenase complex (Halim et al 2010) and a low rate of
NADH shuttling into mitochondria in astrocytes (Berkich
et al 2007 Neves et al 2012) Despite the differences in
basal rates of glucose consumption and lactate release in
cultured astrocytes and neurons application of formaldehyde
signi1047297cantly increases these rates in both types of brain cells
(Tulpule and Dringen 2012 Tulpule et al 2013) However
the extent of stimulation of glycolytic 1047298ux in formaldehyde-
exposed cells compared to the basal condition differs
between the culture types investigated For example at a
formaldehyde concentration of 05 mM the lactate release
and glucose consumption rates were doubled in cultured
neurons (Tulpule et al 2013) while this concentration of
formaldehyde did not affect glycolysis in cultured astrocytes
(Tulpule and Dringen 2012) Astrocytes had to be exposed to
1 mM formaldehyde to elevate glycolysis by 50 (Tulpule
and Dringen 2012)
The accelerated glycolysis in formaldehyde-exposed neu-
ral cells is likely to be caused by the formaldehyde-derived
formate which is known to inhibit mitochondrial cytochrome
c oxidase (Nicholls 1975 Wallace et al 1997) This view is
supported by the observation that incubation of astrocytes
with formaldehyde for 90 min is required for the accelerated
lactate release to persist even after removal of formaldehyde
(Tulpule and Dringen 2012) This long delay most likely
re1047298ects the slow mitochondrial accumulation of formalde-
hyde-derived formate to concentrations that are suf 1047297cient to
inactivate respiration as most of the formate is ef 1047297cientlyexported from astrocytes Moreover the persistent lactate
release of astrocytes exposed to formaldehyde was not
further enhanced by application of azide an inhibitor of
mitochondrial cytochrome c oxidase (Tulpule and Dringen
2012) Thus formaldehyde-derived formate is likely to
stimulate glycolytic 1047298ux as a consequence of an inhibited
respiration as also other inhibitors of respiratory chain
complexes stimulate glycolytic lactate production in cultured
astrocytes and neurons (Pauwels et al 1985 Scheiber and
Dringen 2011)
Formaldehyde-accelerated glutathione export
GSH is an important antioxidant (Lushchak 2012 Schmidt
and Dringen 2012 Lu 2013) that is also involved in the
formaldehyde oxidation catalyzed by ADH3 (Fig 1) Under
basal conditions cultured astrocytes and neurons as well as
cells of the oligodendroglial cell line OLN-93 export GSH
although with variable rates (Tulpule and Dringen 2011
Tulpule et al 2012 2013) Formaldehyde treatment stimu-
lated GSH export from all three types of cultured neural cells
without severely altering the ratio of GSH to glutathione
disul1047297de (GSSG) (Tulpule and Dringen 2011 Tulpule et al
2012 2013) This accelerated GSH export from formalde-
hyde-treated neural cells is mediated by multidrug resistance
Table 2 Consequences of a formaldehyde exposure of rodent brain cells in vivo and in vitro
References
In vivo
Decrease in the number of neuron Gurel et al (2005) Aslan et al (2006) Sarsilmaz et al (2007)Decreased level of GSH Lu et al (2008)
Lowered levels of superoxide dismutase and catalase Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in levels of nitric oxide malondialdehyde
and protein carbonyls
Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in apoptotic events Zararsiz et al (2006 2007)
De1047297cit in memory and learning Pitten et al (2000) Usanmaz et al (2002) Malek et al (2003)
Sorg et al (2004) Lu et al (2008) Turkoglu et al (2008)
Tong et al (2011 2013a b)
In vitro
Elevated glycolysis in neurons and astrocytes Tulpule and Dringen (2012) Tulpule et al (2013)
Mrp1-stimulated GSH export from neurons and astrocytes Tulpule and Dringen (2011) Tulpule et al (2013)
Decreased gl utamate uptake in cultured astrocytes Song et al (2010)
Lower expression of neuronal NMDA receptor subunits Tong et al (2013a)
The articles by Lu et al (2008) Usanmaz et al (2002) and Tong et al (2011) describe data that have been obtained on mice whereas all other
studies were performed on rats or rat brain cells
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 11
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 615
protein (Mrp) 1 (Tulpule and Dringen 2011 Tulpule et al
2012 2013) Mrp1 is a member of ATP-binding cassette
transporters and transports besides GSH a wide array of
substrates including GSSG and GSH conjugates (Keppler
2011 Yin and Zhang 2011) The potential of formaldehydeto accelerate GSH export differs between different brain cell
culture types For example exposure to 05 mM formalde-
hyde increased the respective GSH export rates of cultured
astrocytes neurons and OLN-93 cells by 10- 5- and 20-fold
respectively (Tulpule and Dringen 2011 Tulpule et al 2012
2013) However half-maximal cellular GSH depletions were
observed at similar incubation parameters for all types of
neural cells after incubation for 1 h with 03 mM formalde-
hyde (Tulpule and Dringen 2011 Tulpule et al 2012 2013)
Formaldehyde exposure does not impair the capacity of
neural cells to synthesize GSH At least formaldehyde-treated
neurons restored their cellular GSH levels after application of
amino acid precursors for GSH synthesis (Tulpule et al
2013)
The molecular mechanism involved in the formaldehyde-
accelerated Mrp1-mediated GSH export from neural cells is
not resolved so far Since the stimulation of GSH export is
observed within minutes after formaldehyde application
(Tulpule and Dringen 2011 Tulpule et al 2012 2013)
de novo synthesis of Mrp1 is unlikely to explain the
stimulated GSH ef 1047298ux Furthermore the 1047297nding that removal
of formaldehyde instantly decelerates the stimulated GSH
export (Tulpule and Dringen 2011 Tulpule et al 2012
2013) indicates that the mechanism responsible for formal-
dehyde-accelerated GSH export is quickly reversibleAssuming that cellular GSH is the transported Mrp1
substrate (Fig 2a) formaldehyde could stimulate GSH
export by a reversible covalent activation of this transporter
Alternatively a formaldehyde-induced recruitment of intra-
cellular Mrp1 molecules into the cell membrane could
explain the accelerated GSH export Such a reversible
translocation of Mrp1 from the Golgi to the cell surface
has been reported for cultured astrocytes treated with
bilirubin (Gennuso et al 2004)
Mrp1 ef 1047297ciently exports GSH conjugates (Keppler 2011
Yin and Zhang 2011) As the formaldehyde metabolism in
neural cells involves the generation of the GSH conjugatesS-hydroxymethyl GSH and S-formyl GSH (Fig 1) these
conjugates could also serve as substrates of Mrp1 (Fig 2b)
Since both conjugates are known to be labile (Ahmed and
Ahmed 1978 Uotila 1981) they are likely to disintegrate
into GSH and formaldehyde or formate immediately after
being exported
Direct experimental evidence that discriminates between
the potential two mechanisms (Fig 2) that may be involved
in the formaldehyde-induced accelerated GSH export via
Mrp1 is missing so far However determination of the
kinetic parameters for the GSH export from astrocytes
revealed that the K M-values of the basal as well as the
formaldehyde-accelerated GSH export from astrocytes are
identical (about 100 nmolmg or 25 mM) but that the
V max-value for the stimulated GSH export is eightfold higher
than that for the basal GSH export (Tulpule et al 2012)
These data suggest that at least for formaldehyde-treated
astrocytes GSH rather than a GSH conjugate is exported via
Mrp1 since the K M-values of Mrp1 for its substrate GSH are
normally higher than 5 mM while that for GSH conjugates
are below 1 mM (Burg et al 2002 Cole and Deeley 2006
Deeley and Cole 2006)
Application of formaldehyde does not deprive the cells
completely of their GSH and about 5 residual GSH still
remains within neural cells (Tulpule and Dringen 2011Tulpule et al 2012 2013) In cultured astrocytes this low
cellular GSH content represents a residual GSH concentra-
tion of about 04 mM (Dringen and Hamprecht 1998) which
will be suf 1047297cient to drive ADH3-catalyzed GSH-dependent
formaldehyde oxidation since the K M-value of ADH3 for
S-hydroxymethyl GSH is less than 10 lM (Casanova-
Schmitz et al 1984 Heck et al 1990) and this reaction
(a) (b)
Fig 2 Potential mechanisms involved in
formaldehyde-stimulated glutathione (GSH)
export from brain cells (a) Formaldehyde
directlystimulatesMrp1-mediatedGSH export
(b) The GSH conjugates S-hydroxymethyl
GSH andor S-formyl GSH which are
intermediates of cellular formaldehyde
metabolism are exported by Mrp1 The
labile conjugates immediately disintegrate
after export to generate GSH
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
12 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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involves recycling of GSH (Fig 1) Thus the stimulated
GSH export is unlikely to compromise GSH-dependent
formaldehyde oxidation
Evidence for the role of formaldehyde in pathology
In healthy individuals the formaldehyde concentration in the
blood has been reported to be around 01 mM (Heck and
Casanova 2004) while that in the brain is about 02 mM
(hippocampus) and 04 mM (cortex) (Tong et al 2013a)
These levels of formaldehyde represent the normal phy-
siological balance between formaldehyde-generating and
formaldehyde-disposing processes However an increased
activity of formaldehyde-generating enzymes or an acute
exposure to high amounts of exogenous formaldehyde
without a concurrent elevation in the capacity to clear
formaldehyde will raise formaldehyde level in the body and
will lead to formaldehyde stress (He et al 2010) Indeed an
increased expressionactivity of the formaldehyde-generating
enzymes VAP1SSAO LSD1 and JHDM has been reported
for various diseases (Table 3) While a broad spectrum of
pathological conditions are associated with elevated levels of
VAP1SSAO an increase in the expression of the histone
demethylases has especially been observed in different types
of cancer (Table 3) The elevated expression of formalde-
hyde-generating enzymes is accompanied by increased
formaldehyde levels in diabetic rats (Tong et al 2013a) in
cancer tissue (Tong et al 2010) and in some human cancer
cell lines (Kato et al 2001 Tong et al 2010)
Increased expression of formaldehyde-generating enzymes
(Table 3) as well as elevated formaldehyde levels have also
been reported in brains of patients suffering from neurode-
generative diseases like Alzheimer rsquos disease (AD) or multi-
ple sclerosis (MS) (Khokhlov et al 1989 cited in Miao andHe 2012 Tong et al 2011 2013a) Some hypotheses have
been postulated that link the increase in formaldehyde level
to neuropathology For example some human subjects who
suffered from methanol poisoning developed symptoms of
MS which has been discussed to be an effect of methanol
oxidation to formaldehyde and the subsequent modi1047297cation
of proteins resulting in an immune reaction (Schwyzer and
Henzi 1983 Henzi 1984) Along that line it was discussed
that formaldehyde methylates proteins like tau (in AD) or
myelin basic protein (in MS) which in turn elicits an immune
response by the body that is characteristic for these diseases
(Monte 2010 Lu et al 2013) Also inhibition of SSAO in a
murine model of MS has been shown to reduce the incidence
and severity of this disease (Wang et al 2006) which could
at least partly be the consequence of a lowered formaldehyde
generation Moreover formaldehyde exposure has been
implicated to be a risk factor for the development of
amyotrophic lateral sclerosis (Weisskopf et al 2009) a
disease that is characterized by degeneration of motor
neurons (Kiernan et al 2011)
Formaldehyde-induced alterations in neuralmetabolism as potential contributors toneurodegeneration
Figure 3 summarizes the current knowledge on formalde-
hyde metabolism and on formaldehyde-induced alterations in
the glucose and GSH metabolism of neural cells The
potential of cultured brain cells to ef 1047297ciently metabolize
formaldehyde suggests that also the cells in brain deal quite
well with the moderate amounts of formaldehyde that are
generated under physiological conditions Similar to liver
cells brain cells are likely to use both cytosolic and
mitochondrial pathways for formaldehyde oxidation to
formate and further to carbon dioxide (Figs 1 and 3)
Cultured brain cells ef 1047297ciently produce and export glyco-
lytically generated lactate and also release GSH into the
medium although the basal rates of glycolysis and GSH
export differ between different types of neural cells (Tulpule
and Dringen 2011 2012 Tulpule et al 2012 2013) These
pathways are not affected by low concentrations of formal-
dehyde but as soon as formaldehyde levels are increased in
pathological conditions an accelerated generation of formate
is likely to stimulate glycolytic 1047298ux by inhibition of the
mitochondrial respiration (Fig 3) In addition an excess of
formaldehyde deprives brain cells of GSH by stimulating
Mrp1-mediated GSH export (Fig 3) Although caution should
be exercised while extrapolating in vitro data to the situation
in the brain a speculation on potential consequences of
Table 3 Elevation in expression or activity of formaldehyde-generat-
ing enzymes in human diseases
Enzyme Disease References
SSAOVAP1 Alzheimer rsquos disease Ferrer et al (2002) del Mar
Hernandez et al (2005)
Unzeta et al (2007)
Multiple sclerosis Airas et al (2006)
Heart disease Boomsma et al (2000 2005)
Diabetes mellitus
and diabetic
complications
Meszaros et al (1999)
Gr euroonvall-Nordquist
et al (2001) Karadi et al(2002) Boomsma et al
(2005) Obata (2006)
Chronic liver disease Kurkijarvi et al (2000)
LSD1JHDM Sarcoma Schildhaus et al (2011)
Bennani-Baiti et al (2012)
Peripheral nerve
sheath tumor
Schildhaus et al (2011)
Neuroblastoma Schulte et al (2009)
Bladder cancer Hayami et al (2010 2011)
Breast cancer Lim et al (2010)
Prost ate cancer Kahl et al (2006) Xiang
et al (2007)
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elevated formaldehyde levels in brain on the cellular metab-
olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of
cultured brain cells (01 ndash 1 mM) are in the concentration
range reported for the normal brain (02 ndash 04 mM) Thus mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig 4 Astrocytes and neurons in brain are likely to
ef 1047297ciently metabolize an excess of formaldehyde as also
reported for brain homogenates (Iborra et al 1992) Subse-
quently the formate generated from formaldehyde is either
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain
cells to at least transiently meet their energy demand
However prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al 2007) Besides this impairment of energy
metabolism formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003 Rose 2010) which would subsequently
induce astrocytic swelling impairment of neuronal signal
Fig 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the
generated formate is exported while a fraction is further oxidized to
carbon dioxide Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites
Fig 4 Potential consequences of an
excess of formaldehyde in brain Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed
indirect consequences (dark gray squares)
that 1047297nally lead to the adverse effects
reported for formaldehyde exposure
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
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Conflict of interest
The authors have no con1047298ict of interest to declare
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Formaldehyde in brain 17
7212019 Journal of Neurochemistry
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Environ Health 40 254 ndash 260
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in folate metabolism Chem Biol Interact 178 84 ndash 93
Krupenko N I Dubard M E Strickland K C Moxley K M Oleinik
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Kurkijarvi R Yegutkin G G Gunson B K Jalkanen S Salmi M and
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Laitinen J Makela M Mikkola J and Huttu I (2010) Fire 1047297ghting
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Lee E S Chen H Hardman C Simm A and Charlton C (2008)
Excessive S-adenosyl-L-methionine-dependent methylation
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Sci 83 821 ndash 827
Lee M Schwab C and McGeer P L (2011) Astrocytes are GABAergic
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Leuner K Muller W E and Reichert A S (2012) From mitochondrial
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193
Lewerenz J Dargusch R and Maher P (2010) Lactacidosis modulates
glutathione metabolism and oxidative glutamate toxicity
J Neurochem 113 502 ndash 514
Li F Liu X Su Z and Sun R (2011) Acidosis leads to brain
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Biochem Biophys Res Commun 410 775 ndash 779
Li F Gong Q Dong H and Shi J (2012) Resveratrol a neuroprotective
supplement for Alzheimer rsquos disease Curr Pharm Des 18 27 ndash 33
Lim S Janzer A Becker A Zimmer A Schule R Buettner R and
Kirfel J (2010) Lysine-speci1047297c demethylase 1 (LSD1) is highly
expressed in ER-negative breast cancers and a biomarker
predicting aggressive biology Carcinogenesis 31 512 ndash 520
Lu S C (2013) Glutathione synthesis Biochim Biophys Acta 18303143 ndash 3153
Lu Z Li C M Qiao Y Yan Y and Yang X (2008) Effect of inhaled
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83
Lu J Li C Su T Liu Y and He R (2013) Formaldehyde induces
hyperphosphorylation and polymerization of Tau protein both
in vitro and in vivo Biochim Biophys Acta 1830 4102 ndash 4116
Luo F C Zhou J Lv T Qi L Wang S D Nakamura H Yodoi J and
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MacAllister S L Choi J Dedina L and OrsquoBrien P J (2011) Metabolic
mechanisms of methanolformaldehyde in isolated rat hepatocytes
Carbonyl-metabolizing enzymes versus oxidative stress Chem
Biol Interact 191 308 ndash 314
MacFarlane A J Perry C A Girnary H H Gao D Allen R H
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Mahad D Ziabreva I Lassmann H and Turnbull D (2008)
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Malek F A Moritz K U and Fanghanel J (2003) A study on speci1047297c
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Postsynaptic fall in intracellular pH and increase in surface pH
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Meszaros Z Szombathy T Raimondi L Karadi I Romics L and
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Metabolism 48 113 ndash 117
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Metz B Kersten G F Baart G J de Jong A Meiring H ten Hove J
van Steenbergen M J Hennink W E Crommelin D J and
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Chem 17 815 ndash 822
Miao J and He R (2012) Chronic formaldehyde-mediated impairments
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Monte W C (2010) Methanol a chemical Trojan horse as the root of the
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Mukherjee S and Manahan-Vaughan D (2013) Role of metabotropic
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Nazarian A Hermannsson B J Muller J Zurakowski D and Snyder
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18 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase
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Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
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Oldham M C Konopka G Iwamoto K Langfelder P Kato T
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the transcriptome in the human brain Nat Neurosci 11 1271 ndash
1282
Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide
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OrsquoSullivan J Unzeta M Healy J OrsquoSullivan M I Davey G and
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Pitten F A Kramer A Herrmann K Breme I and Koch S (2000)
Formaldehyde neurotoxicity in animal experiments Pathol ResPract 196 193 ndash 198
Prasannan P Pike S Peng K Shane B and Appling D R (2003)
Human mitochondrial C1-tetrahydrofolate synthase gene structure
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Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
high concentrations of extracellular reduced glutathione
Neuroscience 91 463 ndash 470
Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
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Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
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Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
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Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
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Song M S Baker G B Dursun S M and Todd K G (2010) The
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Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
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Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
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Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
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Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
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and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash
74
Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
less support implications for Alzheimer rsquos disease Neurobiol
Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
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J Neurosci 30 2547 ndash 2558
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Formaldehyde in brain 19
7212019 Journal of Neurochemistry
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Stewart M J Malek K and Crabb D W (1996) Distribution of
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Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
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Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
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Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
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Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
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Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
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Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
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Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
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Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
inversely correlated to mini mental state examination scores in
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Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
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Tong Z Han C Luo W et al (2013b) Aging-associated excess
formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
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Tulpule K and Dringen R (2012) Formate generated by cellular
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cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
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Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
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J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
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Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
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Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
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Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
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diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
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Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
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Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
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Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
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20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 515
in vitro (Table 2) Recently it was demonstrated that
formaldehyde in the concentration range between 01 mM
and 1 mM strongly affects basal metabolic properties of
cultured astrocytes and neurons that is formaldehyde
stimulates glycolytic 1047298ux and the export of the antioxidative
tripeptide GSH from brain cells
Formaldehyde-stimulated glycolysisAstrocytes are more glycolytic than neurons (Bola~nos et al
2010) a feature which has been attributed to expression of
the glycolysis-promoting enzyme PFKFB3 in astrocytes
(Herrero-Mendez et al 2009) an inhibited pyruvate dehy-
drogenase complex (Halim et al 2010) and a low rate of
NADH shuttling into mitochondria in astrocytes (Berkich
et al 2007 Neves et al 2012) Despite the differences in
basal rates of glucose consumption and lactate release in
cultured astrocytes and neurons application of formaldehyde
signi1047297cantly increases these rates in both types of brain cells
(Tulpule and Dringen 2012 Tulpule et al 2013) However
the extent of stimulation of glycolytic 1047298ux in formaldehyde-
exposed cells compared to the basal condition differs
between the culture types investigated For example at a
formaldehyde concentration of 05 mM the lactate release
and glucose consumption rates were doubled in cultured
neurons (Tulpule et al 2013) while this concentration of
formaldehyde did not affect glycolysis in cultured astrocytes
(Tulpule and Dringen 2012) Astrocytes had to be exposed to
1 mM formaldehyde to elevate glycolysis by 50 (Tulpule
and Dringen 2012)
The accelerated glycolysis in formaldehyde-exposed neu-
ral cells is likely to be caused by the formaldehyde-derived
formate which is known to inhibit mitochondrial cytochrome
c oxidase (Nicholls 1975 Wallace et al 1997) This view is
supported by the observation that incubation of astrocytes
with formaldehyde for 90 min is required for the accelerated
lactate release to persist even after removal of formaldehyde
(Tulpule and Dringen 2012) This long delay most likely
re1047298ects the slow mitochondrial accumulation of formalde-
hyde-derived formate to concentrations that are suf 1047297cient to
inactivate respiration as most of the formate is ef 1047297cientlyexported from astrocytes Moreover the persistent lactate
release of astrocytes exposed to formaldehyde was not
further enhanced by application of azide an inhibitor of
mitochondrial cytochrome c oxidase (Tulpule and Dringen
2012) Thus formaldehyde-derived formate is likely to
stimulate glycolytic 1047298ux as a consequence of an inhibited
respiration as also other inhibitors of respiratory chain
complexes stimulate glycolytic lactate production in cultured
astrocytes and neurons (Pauwels et al 1985 Scheiber and
Dringen 2011)
Formaldehyde-accelerated glutathione export
GSH is an important antioxidant (Lushchak 2012 Schmidt
and Dringen 2012 Lu 2013) that is also involved in the
formaldehyde oxidation catalyzed by ADH3 (Fig 1) Under
basal conditions cultured astrocytes and neurons as well as
cells of the oligodendroglial cell line OLN-93 export GSH
although with variable rates (Tulpule and Dringen 2011
Tulpule et al 2012 2013) Formaldehyde treatment stimu-
lated GSH export from all three types of cultured neural cells
without severely altering the ratio of GSH to glutathione
disul1047297de (GSSG) (Tulpule and Dringen 2011 Tulpule et al
2012 2013) This accelerated GSH export from formalde-
hyde-treated neural cells is mediated by multidrug resistance
Table 2 Consequences of a formaldehyde exposure of rodent brain cells in vivo and in vitro
References
In vivo
Decrease in the number of neuron Gurel et al (2005) Aslan et al (2006) Sarsilmaz et al (2007)Decreased level of GSH Lu et al (2008)
Lowered levels of superoxide dismutase and catalase Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in levels of nitric oxide malondialdehyde
and protein carbonyls
Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)
Songur et al (2008)
Increase in apoptotic events Zararsiz et al (2006 2007)
De1047297cit in memory and learning Pitten et al (2000) Usanmaz et al (2002) Malek et al (2003)
Sorg et al (2004) Lu et al (2008) Turkoglu et al (2008)
Tong et al (2011 2013a b)
In vitro
Elevated glycolysis in neurons and astrocytes Tulpule and Dringen (2012) Tulpule et al (2013)
Mrp1-stimulated GSH export from neurons and astrocytes Tulpule and Dringen (2011) Tulpule et al (2013)
Decreased gl utamate uptake in cultured astrocytes Song et al (2010)
Lower expression of neuronal NMDA receptor subunits Tong et al (2013a)
The articles by Lu et al (2008) Usanmaz et al (2002) and Tong et al (2011) describe data that have been obtained on mice whereas all other
studies were performed on rats or rat brain cells
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 11
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 615
protein (Mrp) 1 (Tulpule and Dringen 2011 Tulpule et al
2012 2013) Mrp1 is a member of ATP-binding cassette
transporters and transports besides GSH a wide array of
substrates including GSSG and GSH conjugates (Keppler
2011 Yin and Zhang 2011) The potential of formaldehydeto accelerate GSH export differs between different brain cell
culture types For example exposure to 05 mM formalde-
hyde increased the respective GSH export rates of cultured
astrocytes neurons and OLN-93 cells by 10- 5- and 20-fold
respectively (Tulpule and Dringen 2011 Tulpule et al 2012
2013) However half-maximal cellular GSH depletions were
observed at similar incubation parameters for all types of
neural cells after incubation for 1 h with 03 mM formalde-
hyde (Tulpule and Dringen 2011 Tulpule et al 2012 2013)
Formaldehyde exposure does not impair the capacity of
neural cells to synthesize GSH At least formaldehyde-treated
neurons restored their cellular GSH levels after application of
amino acid precursors for GSH synthesis (Tulpule et al
2013)
The molecular mechanism involved in the formaldehyde-
accelerated Mrp1-mediated GSH export from neural cells is
not resolved so far Since the stimulation of GSH export is
observed within minutes after formaldehyde application
(Tulpule and Dringen 2011 Tulpule et al 2012 2013)
de novo synthesis of Mrp1 is unlikely to explain the
stimulated GSH ef 1047298ux Furthermore the 1047297nding that removal
of formaldehyde instantly decelerates the stimulated GSH
export (Tulpule and Dringen 2011 Tulpule et al 2012
2013) indicates that the mechanism responsible for formal-
dehyde-accelerated GSH export is quickly reversibleAssuming that cellular GSH is the transported Mrp1
substrate (Fig 2a) formaldehyde could stimulate GSH
export by a reversible covalent activation of this transporter
Alternatively a formaldehyde-induced recruitment of intra-
cellular Mrp1 molecules into the cell membrane could
explain the accelerated GSH export Such a reversible
translocation of Mrp1 from the Golgi to the cell surface
has been reported for cultured astrocytes treated with
bilirubin (Gennuso et al 2004)
Mrp1 ef 1047297ciently exports GSH conjugates (Keppler 2011
Yin and Zhang 2011) As the formaldehyde metabolism in
neural cells involves the generation of the GSH conjugatesS-hydroxymethyl GSH and S-formyl GSH (Fig 1) these
conjugates could also serve as substrates of Mrp1 (Fig 2b)
Since both conjugates are known to be labile (Ahmed and
Ahmed 1978 Uotila 1981) they are likely to disintegrate
into GSH and formaldehyde or formate immediately after
being exported
Direct experimental evidence that discriminates between
the potential two mechanisms (Fig 2) that may be involved
in the formaldehyde-induced accelerated GSH export via
Mrp1 is missing so far However determination of the
kinetic parameters for the GSH export from astrocytes
revealed that the K M-values of the basal as well as the
formaldehyde-accelerated GSH export from astrocytes are
identical (about 100 nmolmg or 25 mM) but that the
V max-value for the stimulated GSH export is eightfold higher
than that for the basal GSH export (Tulpule et al 2012)
These data suggest that at least for formaldehyde-treated
astrocytes GSH rather than a GSH conjugate is exported via
Mrp1 since the K M-values of Mrp1 for its substrate GSH are
normally higher than 5 mM while that for GSH conjugates
are below 1 mM (Burg et al 2002 Cole and Deeley 2006
Deeley and Cole 2006)
Application of formaldehyde does not deprive the cells
completely of their GSH and about 5 residual GSH still
remains within neural cells (Tulpule and Dringen 2011Tulpule et al 2012 2013) In cultured astrocytes this low
cellular GSH content represents a residual GSH concentra-
tion of about 04 mM (Dringen and Hamprecht 1998) which
will be suf 1047297cient to drive ADH3-catalyzed GSH-dependent
formaldehyde oxidation since the K M-value of ADH3 for
S-hydroxymethyl GSH is less than 10 lM (Casanova-
Schmitz et al 1984 Heck et al 1990) and this reaction
(a) (b)
Fig 2 Potential mechanisms involved in
formaldehyde-stimulated glutathione (GSH)
export from brain cells (a) Formaldehyde
directlystimulatesMrp1-mediatedGSH export
(b) The GSH conjugates S-hydroxymethyl
GSH andor S-formyl GSH which are
intermediates of cellular formaldehyde
metabolism are exported by Mrp1 The
labile conjugates immediately disintegrate
after export to generate GSH
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
12 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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involves recycling of GSH (Fig 1) Thus the stimulated
GSH export is unlikely to compromise GSH-dependent
formaldehyde oxidation
Evidence for the role of formaldehyde in pathology
In healthy individuals the formaldehyde concentration in the
blood has been reported to be around 01 mM (Heck and
Casanova 2004) while that in the brain is about 02 mM
(hippocampus) and 04 mM (cortex) (Tong et al 2013a)
These levels of formaldehyde represent the normal phy-
siological balance between formaldehyde-generating and
formaldehyde-disposing processes However an increased
activity of formaldehyde-generating enzymes or an acute
exposure to high amounts of exogenous formaldehyde
without a concurrent elevation in the capacity to clear
formaldehyde will raise formaldehyde level in the body and
will lead to formaldehyde stress (He et al 2010) Indeed an
increased expressionactivity of the formaldehyde-generating
enzymes VAP1SSAO LSD1 and JHDM has been reported
for various diseases (Table 3) While a broad spectrum of
pathological conditions are associated with elevated levels of
VAP1SSAO an increase in the expression of the histone
demethylases has especially been observed in different types
of cancer (Table 3) The elevated expression of formalde-
hyde-generating enzymes is accompanied by increased
formaldehyde levels in diabetic rats (Tong et al 2013a) in
cancer tissue (Tong et al 2010) and in some human cancer
cell lines (Kato et al 2001 Tong et al 2010)
Increased expression of formaldehyde-generating enzymes
(Table 3) as well as elevated formaldehyde levels have also
been reported in brains of patients suffering from neurode-
generative diseases like Alzheimer rsquos disease (AD) or multi-
ple sclerosis (MS) (Khokhlov et al 1989 cited in Miao andHe 2012 Tong et al 2011 2013a) Some hypotheses have
been postulated that link the increase in formaldehyde level
to neuropathology For example some human subjects who
suffered from methanol poisoning developed symptoms of
MS which has been discussed to be an effect of methanol
oxidation to formaldehyde and the subsequent modi1047297cation
of proteins resulting in an immune reaction (Schwyzer and
Henzi 1983 Henzi 1984) Along that line it was discussed
that formaldehyde methylates proteins like tau (in AD) or
myelin basic protein (in MS) which in turn elicits an immune
response by the body that is characteristic for these diseases
(Monte 2010 Lu et al 2013) Also inhibition of SSAO in a
murine model of MS has been shown to reduce the incidence
and severity of this disease (Wang et al 2006) which could
at least partly be the consequence of a lowered formaldehyde
generation Moreover formaldehyde exposure has been
implicated to be a risk factor for the development of
amyotrophic lateral sclerosis (Weisskopf et al 2009) a
disease that is characterized by degeneration of motor
neurons (Kiernan et al 2011)
Formaldehyde-induced alterations in neuralmetabolism as potential contributors toneurodegeneration
Figure 3 summarizes the current knowledge on formalde-
hyde metabolism and on formaldehyde-induced alterations in
the glucose and GSH metabolism of neural cells The
potential of cultured brain cells to ef 1047297ciently metabolize
formaldehyde suggests that also the cells in brain deal quite
well with the moderate amounts of formaldehyde that are
generated under physiological conditions Similar to liver
cells brain cells are likely to use both cytosolic and
mitochondrial pathways for formaldehyde oxidation to
formate and further to carbon dioxide (Figs 1 and 3)
Cultured brain cells ef 1047297ciently produce and export glyco-
lytically generated lactate and also release GSH into the
medium although the basal rates of glycolysis and GSH
export differ between different types of neural cells (Tulpule
and Dringen 2011 2012 Tulpule et al 2012 2013) These
pathways are not affected by low concentrations of formal-
dehyde but as soon as formaldehyde levels are increased in
pathological conditions an accelerated generation of formate
is likely to stimulate glycolytic 1047298ux by inhibition of the
mitochondrial respiration (Fig 3) In addition an excess of
formaldehyde deprives brain cells of GSH by stimulating
Mrp1-mediated GSH export (Fig 3) Although caution should
be exercised while extrapolating in vitro data to the situation
in the brain a speculation on potential consequences of
Table 3 Elevation in expression or activity of formaldehyde-generat-
ing enzymes in human diseases
Enzyme Disease References
SSAOVAP1 Alzheimer rsquos disease Ferrer et al (2002) del Mar
Hernandez et al (2005)
Unzeta et al (2007)
Multiple sclerosis Airas et al (2006)
Heart disease Boomsma et al (2000 2005)
Diabetes mellitus
and diabetic
complications
Meszaros et al (1999)
Gr euroonvall-Nordquist
et al (2001) Karadi et al(2002) Boomsma et al
(2005) Obata (2006)
Chronic liver disease Kurkijarvi et al (2000)
LSD1JHDM Sarcoma Schildhaus et al (2011)
Bennani-Baiti et al (2012)
Peripheral nerve
sheath tumor
Schildhaus et al (2011)
Neuroblastoma Schulte et al (2009)
Bladder cancer Hayami et al (2010 2011)
Breast cancer Lim et al (2010)
Prost ate cancer Kahl et al (2006) Xiang
et al (2007)
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elevated formaldehyde levels in brain on the cellular metab-
olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of
cultured brain cells (01 ndash 1 mM) are in the concentration
range reported for the normal brain (02 ndash 04 mM) Thus mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig 4 Astrocytes and neurons in brain are likely to
ef 1047297ciently metabolize an excess of formaldehyde as also
reported for brain homogenates (Iborra et al 1992) Subse-
quently the formate generated from formaldehyde is either
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain
cells to at least transiently meet their energy demand
However prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al 2007) Besides this impairment of energy
metabolism formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003 Rose 2010) which would subsequently
induce astrocytic swelling impairment of neuronal signal
Fig 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the
generated formate is exported while a fraction is further oxidized to
carbon dioxide Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites
Fig 4 Potential consequences of an
excess of formaldehyde in brain Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed
indirect consequences (dark gray squares)
that 1047297nally lead to the adverse effects
reported for formaldehyde exposure
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
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Conflict of interest
The authors have no con1047298ict of interest to declare
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Kato S Burke P J Koch T H and Bierbaum V M (2001)
Formaldehyde in human cancer cells detection by preconcentration-
chemical ionization mass spectrometry Anal Chem 73 2992 ndash
2997
Keppler D (2011) Multidrug resistance proteins (MRPs ABCCs)
importance for pathophysiology and drug therapy Handb Exp
Pharmacol 201 299 ndash 323
Khokhlov A P Zavalishin I A Savchenko I N and Dziuba A N
(1989) Disorders of formaldehyde metabolism and its metabolic
precursors in patients with multiple sclerosis Zh Nevropatol
Psikhiatr Im S S Korsakova 89 45 ndash 48
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 17
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1215
Kiernan J A (2000) Formaldehyde formalin paraformaldehyde and
glutaraldehyde what they are and what they do Microsc Today 1
8 ndash 12
Kiernan M C Vucic S Cheah B C Turner M R Eisen A Hardiman
O Burrell J R and Zoing M C (2011) Amyotrophic lateral
sclerosis Lancet 377 942 ndash 955Kilburn K H Seidman B C and Warshaw R (1985a) Neurobehavioral
and respiratory symptoms of formaldehyde and xylene exposure in
histology technicians Arch Environ Health 40 229 ndash 233
Kilburn K H Warshaw R Boylen C T Johnson S J Seidman B
Sinclair R and Takaro T Jr (1985b) Pulmonary and
neurobehavioral effects of formaldehyde exposure Arch
Environ Health 40 254 ndash 260
Krupenko S A (2009) FDH an aldehyde dehydrogenase fusion enzyme
in folate metabolism Chem Biol Interact 178 84 ndash 93
Krupenko N I Dubard M E Strickland K C Moxley K M Oleinik
N V and Krupenko S A (2010) ALDH1L2 is the mitochondrial
homolog of 10-formyltetrahydrofolate dehydrogenase J Biol
Chem 285 23056 ndash 23063
Kurkijarvi R Yegutkin G G Gunson B K Jalkanen S Salmi M and
Adams D H (2000) Circulating soluble vascular adhesion protein1 accounts for the increased serum monoamine oxidase activity in
chronic liver disease Gastroenterology 119 1096 ndash 1103
Laitinen J Makela M Mikkola J and Huttu I (2010) Fire 1047297ghting
trainersrsquo exposure to carcinogenic agents in smoke diving
simulators Toxicol Lett 192 61 ndash 65
Lee E S Chen H Hardman C Simm A and Charlton C (2008)
Excessive S-adenosyl-L-methionine-dependent methylation
increases levels of methanol formaldehyde and formic acid in rat
brain striatal homogenates possible role in S-adenosyl-
L-methionine-induced Parkinsonrsquos disease-like disorders Life
Sci 83 821 ndash 827
Lee M Schwab C and McGeer P L (2011) Astrocytes are GABAergic
cells that modulate microglial activity Glia 59 152 ndash 165
Leuner K Muller W E and Reichert A S (2012) From mitochondrial
dysfunction to amyloid beta formation novel insights into thepathogenesis of Alzheimer rsquos disease Mol Neurobiol 46 186 ndash
193
Lewerenz J Dargusch R and Maher P (2010) Lactacidosis modulates
glutathione metabolism and oxidative glutamate toxicity
J Neurochem 113 502 ndash 514
Li F Liu X Su Z and Sun R (2011) Acidosis leads to brain
dysfunctions through impairing cortical GABAergic neurons
Biochem Biophys Res Commun 410 775 ndash 779
Li F Gong Q Dong H and Shi J (2012) Resveratrol a neuroprotective
supplement for Alzheimer rsquos disease Curr Pharm Des 18 27 ndash 33
Lim S Janzer A Becker A Zimmer A Schule R Buettner R and
Kirfel J (2010) Lysine-speci1047297c demethylase 1 (LSD1) is highly
expressed in ER-negative breast cancers and a biomarker
predicting aggressive biology Carcinogenesis 31 512 ndash 520
Lu S C (2013) Glutathione synthesis Biochim Biophys Acta 18303143 ndash 3153
Lu Z Li C M Qiao Y Yan Y and Yang X (2008) Effect of inhaled
formaldehyde on learning and memory of mice Indoor Air 18 77 ndash
83
Lu J Li C Su T Liu Y and He R (2013) Formaldehyde induces
hyperphosphorylation and polymerization of Tau protein both
in vitro and in vivo Biochim Biophys Acta 1830 4102 ndash 4116
Luo F C Zhou J Lv T Qi L Wang S D Nakamura H Yodoi J and
Bai J (2012) Induction of endoplasmic reticulum stress and the
modulation of thioredoxin-1 in formaldehyde-induced
neurotoxicity Neurotoxicology 33 290 ndash 298
Lushchak V I (2012) Glutathione homeostasis and functions potential
targets for medical interventions J Amino Acids 2012 736837
MacAllister S L Choi J Dedina L and OrsquoBrien P J (2011) Metabolic
mechanisms of methanolformaldehyde in isolated rat hepatocytes
Carbonyl-metabolizing enzymes versus oxidative stress Chem
Biol Interact 191 308 ndash 314
MacFarlane A J Perry C A Girnary H H Gao D Allen R H
Stabler S P Shane B and Stover P J (2009) Mthfd1 is anessential gene in mice and alters biomarkers of impaired one-
carbon metabolism J Biol Chem 284 1533 ndash 1539
Mahad D Ziabreva I Lassmann H and Turnbull D (2008)
Mitochondrial defects in acute multiple sclerosis lesions Brain
131 1722 ndash 1735
Malek F A Moritz K U and Fanghanel J (2003) A study on speci1047297c
behavioral effects of formaldehyde in the rat J Exp Anim Sci 42
160 ndash 170
del Mar Hernandez M Esteban M Szabo P Boada M and Unzeta M
(2005) Human plasma semicarbazide sensitive amine oxidase
(SSAO) b-amyloid protein and aging Neurosci Lett 384183 ndash 187
Martinez S E Vaglenova J Sabria J Martinez M C Farres J and
Pares X (2001) Distribution of alcohol dehydrogenase mRNA in
the rat central nervous system - consequences for brain ethanol and
retinoid metabolism Eur J Biochem 268 5045 ndash 5056Mason M J Mattsson K Pasternack M Voipio J and Kaila K (1990)
Postsynaptic fall in intracellular pH and increase in surface pH
caused by ef 1047298ux of formate and acetate anions through GABA-
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Meinerz D F Comprasi B Allebrandt J et al (2013) Sub-acute
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effects of N-acetylcysteine Springerplus 2 182
Meszaros Z Szombathy T Raimondi L Karadi I Romics L and
Magyar K (1999) Elevated serum semicarbazide-sensitive amine
oxidase activity in non-insulin-dependent diabetes mellitus
correlation with body mass index and serum triglyceride
Metabolism 48 113 ndash 117
Metz B Kersten G F Hoogerhout P et al (2004) Identi1047297cation of formaldehyde-induced modi1047297cations in proteins reactions with
model peptides J Biol Chem 279 6235 ndash 6243
Metz B Kersten G F Baart G J de Jong A Meiring H ten Hove J
van Steenbergen M J Hennink W E Crommelin D J and
Jiskoot W (2006) Identi1047297cation of formaldehyde-induced
modi1047297cations in proteins reactions with insulin Bioconjug
Chem 17 815 ndash 822
Miao J and He R (2012) Chronic formaldehyde-mediated impairments
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Loh S H Y eds) pp 59 ndash 76 InTech doi 10577234949
Monte W C (2010) Methanol a chemical Trojan horse as the root of the
inscrutable U Med Hypotheses 74 493 ndash 496
Moschen I Broer A Galic S Lang F and Broer S (2012) Signi1047297cance
of short chain fatty acid transport by members of the
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Mukherjee S and Manahan-Vaughan D (2013) Role of metabotropic
glutamate receptors in persistent forms of hippocampal plasticity
and learning Neuropharmacology 66 65 ndash 81
Nazarian A Hermannsson B J Muller J Zurakowski D and Snyder
B D (2009) Effects of tissue preservation on murine bone
mechanical properties J Biomech 42 82 ndash 86
Neves A Costalat R and Pellerin L (2012) Determinants of brain
cell metabolic phenotypes and energy substrate utilization unraveled
with a modeling approach PLoS Comput Biol 8 e1002686
Neymeyer V Tephly T R and Miller M W (1997) Folate and 10-
formyltetrahydrofolate dehydrogenase (FDH) expression in the
central nervous system of the mature rat Brain Res 766 195 ndash 204
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
18 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1315
Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase
Biochem Biophys Res Commun 67 610 ndash 616
Nishimura M and Naito S (2006) Tissue-speci1047297c mRNA expression
pro1047297les of human phase I metabolizing enzymes except for
cytochrome P450 and phase II metabolizing enzymes Drug
Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
(SSAO) activity a review Life Sci 79 417 ndash 422
Obata T and Yamanaka Y (2000) Evidence for existence of
immobilization stress-inducible semicarbazide-sensitive amine
oxidase inhibitor in rat brain cytosol Neurosci Lett 296 58 ndash 60
Oldham M C Konopka G Iwamoto K Langfelder P Kato T
Horvath S and Geschwind D (2008) Functional organization of
the transcriptome in the human brain Nat Neurosci 11 1271 ndash
1282
Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide
diversity of function and pharmacology Neuropharmacology 56
141 ndash 148
OrsquoSullivan J Unzeta M Healy J OrsquoSullivan M I Davey G and
Tipton K F (2004) Semicarbazide-sensitive amine oxidases
enzymes with quite a lot to do Neurotoxicology 25 303 ndash 315Oyama Y Sakai H Arata T Okano Y Akaike N Sakai K and Noda
K (2002) Cytotoxic effects of methanol formaldehyde and
formate on dissociated rat thymocytes a possibility of aspartame
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Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D
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Parnetti L Reboldi G P and Gallai V (2000) Cerebrospinal 1047298uid
pyruvate levels in Alzheimer rsquos disease and vascular dementia
Neurology 54 735 ndash 737
Pauwels P J Opperdoes F R and Trouet A (1985) Effects of
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Pitten F A Kramer A Herrmann K Breme I and Koch S (2000)
Formaldehyde neurotoxicity in animal experiments Pathol ResPract 196 193 ndash 198
Prasannan P Pike S Peng K Shane B and Appling D R (2003)
Human mitochondrial C1-tetrahydrofolate synthase gene structure
tissue distribution of the mRNA and immunolocalization in
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Regan R F and Guo Y P (1999a) Extracellular reduced glutathione
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glucose deprivation Brain Res 817 145 ndash 150
Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
high concentrations of extracellular reduced glutathione
Neuroscience 91 463 ndash 470
Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
Merillon J M and Monti J P (2011) Neuroprotective properties
of resveratrol and derivatives Ann N Y Acad Sci 1215 103 ndash
108Rose C F (2010) Increase brain lactate in hepatic encephalopathy cause
or consequence Neurochem Int 57 389 ndash 394
Ross J M Oberg J Brene S et al (2010) High brain lactate is a
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Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
indoor environment Chem Rev 110 2536 ndash 2572
Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
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formaldehyde exposure on pyramidal cell number volume of cell
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Sasseville D (2004) Hypersensitivity to preservatives Dermatol Ther
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Schad A Fahimi H D Volkl A and Baumgart E (2003) Expression
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immunohistochemistry (IHC)immuno1047298uorescence (IF) J
Histochem Cytochem 51 751 ndash 760
Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux
in cultured astrocytes Neurochem Res 36 894 ndash 903
Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c
demethylase 1 is highly expressed in solitary 1047297brous tumors
synovial sarcomas rhabdomyosarcomas desmoplastic small round
cell tumors and malignant peripheral nerve sheath tumors Hum
Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
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Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
neuroblastoma implications for therapy Cancer Res 69 2065 ndash
2071
Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
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Skrzydlewska E (2003) Toxicological and metabolic consequences of
methanol poisoning Toxicol Mech Methods 13 277 ndash 293
Smith D J and Vainio P J (2007) Targeting vascular adhesion protein-
1 to treat autoimmune and in1047298ammatory diseases Ann N Y Acad
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Sohal R S and Orr W C (2012) The redox stress hypothesis of aging
Free Radic Biol Med 52 539 ndash 555
Song M S Baker G B Dursun S M and Todd K G (2010) The
antidepressant phenelzine protects neurons and astrocytes
against formaldehyde-induced toxicity J Neurochem 1141405 ndash 1413
Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
Ilhan N (2008) The effects of inhaled formaldehyde on oxidant and
antioxidant systems of rat cerebellum during the postnatal
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Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
formaldehyde on the nervous system Rev Environ Contam
Toxicol 203 105 ndash 118
Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
formaldehyde exposure produces enhanced fear conditioning to
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Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
(2009) The janus face of alcohol dehydrogenase 3 Chem Biol
Interact 178 29 ndash 35
Staub F Peters J Kempski O Schneider G H Schurer Land Baethmann A (1993) Swelling of glial cells in lactacidosis
and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash
74
Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
less support implications for Alzheimer rsquos disease Neurobiol
Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
P Cuenod M and Do K Q (2010) Redox dysregulation affects
the ventral but not dorsal hippocampus impairment of
parvalbumin neurons gamma oscillations and related behaviors
J Neurosci 30 2547 ndash 2558
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Formaldehyde in brain 19
7212019 Journal of Neurochemistry
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Stewart M J Malek K and Crabb D W (1996) Distribution of
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Sullivan P G and Brown M R (2005) Mitochondrial aging and
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Biol Psychiatry 29 407 ndash 410
Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
Magistretti P J and Alberini C M (2011) Astrocyte-neuron
lactate transport is required for long-term memory formation Cell
144 810 ndash 823
Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
and health effects Environ Int 35 1210 ndash 1224
Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
neurotoxicity to PC12 cells involving inhibition of paraoxonase-1
expression and activity Clin Exp Pharmacol Physiol 38 208 ndash
214
Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
1041
Thigpen A E West M G and Appling D R (1990) Rat C1-
tetrahydrofolate synthase cDNA isolation tissue-speci1047297c levels of
the mRNA and expression of the protein in yeast J Biol Chem
265 7907 ndash 7913
Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
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Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev
Nutr 30 57 ndash 81
Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
formaldehyde and acidic microenvironment synergistically induce
bone cancer pain PLoS ONE 5 e10234
Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
inversely correlated to mini mental state examination scores in
senile dementia Neurobiol Aging 32 31 ndash 41
Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
R (2013a) Accumulated hippocampal formaldehyde induces age-
dependent memory decline Age (Dordr) 35 583 ndash 596
Tong Z Han C Luo W et al (2013b) Aging-associated excess
formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635
Tulpule K and Dringen R (2012) Formate generated by cellular
oxidation of formaldehyde accelerates the glycolytic 1047298ux in
cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
Neurochem Int 61 1302 ndash 1313
Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
metabolism and formaldehyde-induced stimulation of lactate
production and glutathione export in cultured neurons
J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
performance study Erciyes Med J 30 211 ndash 217
Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74
Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
vasculature pathological synergy of Alzheimer rsquos disease and
diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
(1997) Mitochondria-mediated cell injury Symposium overview
Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 615
protein (Mrp) 1 (Tulpule and Dringen 2011 Tulpule et al
2012 2013) Mrp1 is a member of ATP-binding cassette
transporters and transports besides GSH a wide array of
substrates including GSSG and GSH conjugates (Keppler
2011 Yin and Zhang 2011) The potential of formaldehydeto accelerate GSH export differs between different brain cell
culture types For example exposure to 05 mM formalde-
hyde increased the respective GSH export rates of cultured
astrocytes neurons and OLN-93 cells by 10- 5- and 20-fold
respectively (Tulpule and Dringen 2011 Tulpule et al 2012
2013) However half-maximal cellular GSH depletions were
observed at similar incubation parameters for all types of
neural cells after incubation for 1 h with 03 mM formalde-
hyde (Tulpule and Dringen 2011 Tulpule et al 2012 2013)
Formaldehyde exposure does not impair the capacity of
neural cells to synthesize GSH At least formaldehyde-treated
neurons restored their cellular GSH levels after application of
amino acid precursors for GSH synthesis (Tulpule et al
2013)
The molecular mechanism involved in the formaldehyde-
accelerated Mrp1-mediated GSH export from neural cells is
not resolved so far Since the stimulation of GSH export is
observed within minutes after formaldehyde application
(Tulpule and Dringen 2011 Tulpule et al 2012 2013)
de novo synthesis of Mrp1 is unlikely to explain the
stimulated GSH ef 1047298ux Furthermore the 1047297nding that removal
of formaldehyde instantly decelerates the stimulated GSH
export (Tulpule and Dringen 2011 Tulpule et al 2012
2013) indicates that the mechanism responsible for formal-
dehyde-accelerated GSH export is quickly reversibleAssuming that cellular GSH is the transported Mrp1
substrate (Fig 2a) formaldehyde could stimulate GSH
export by a reversible covalent activation of this transporter
Alternatively a formaldehyde-induced recruitment of intra-
cellular Mrp1 molecules into the cell membrane could
explain the accelerated GSH export Such a reversible
translocation of Mrp1 from the Golgi to the cell surface
has been reported for cultured astrocytes treated with
bilirubin (Gennuso et al 2004)
Mrp1 ef 1047297ciently exports GSH conjugates (Keppler 2011
Yin and Zhang 2011) As the formaldehyde metabolism in
neural cells involves the generation of the GSH conjugatesS-hydroxymethyl GSH and S-formyl GSH (Fig 1) these
conjugates could also serve as substrates of Mrp1 (Fig 2b)
Since both conjugates are known to be labile (Ahmed and
Ahmed 1978 Uotila 1981) they are likely to disintegrate
into GSH and formaldehyde or formate immediately after
being exported
Direct experimental evidence that discriminates between
the potential two mechanisms (Fig 2) that may be involved
in the formaldehyde-induced accelerated GSH export via
Mrp1 is missing so far However determination of the
kinetic parameters for the GSH export from astrocytes
revealed that the K M-values of the basal as well as the
formaldehyde-accelerated GSH export from astrocytes are
identical (about 100 nmolmg or 25 mM) but that the
V max-value for the stimulated GSH export is eightfold higher
than that for the basal GSH export (Tulpule et al 2012)
These data suggest that at least for formaldehyde-treated
astrocytes GSH rather than a GSH conjugate is exported via
Mrp1 since the K M-values of Mrp1 for its substrate GSH are
normally higher than 5 mM while that for GSH conjugates
are below 1 mM (Burg et al 2002 Cole and Deeley 2006
Deeley and Cole 2006)
Application of formaldehyde does not deprive the cells
completely of their GSH and about 5 residual GSH still
remains within neural cells (Tulpule and Dringen 2011Tulpule et al 2012 2013) In cultured astrocytes this low
cellular GSH content represents a residual GSH concentra-
tion of about 04 mM (Dringen and Hamprecht 1998) which
will be suf 1047297cient to drive ADH3-catalyzed GSH-dependent
formaldehyde oxidation since the K M-value of ADH3 for
S-hydroxymethyl GSH is less than 10 lM (Casanova-
Schmitz et al 1984 Heck et al 1990) and this reaction
(a) (b)
Fig 2 Potential mechanisms involved in
formaldehyde-stimulated glutathione (GSH)
export from brain cells (a) Formaldehyde
directlystimulatesMrp1-mediatedGSH export
(b) The GSH conjugates S-hydroxymethyl
GSH andor S-formyl GSH which are
intermediates of cellular formaldehyde
metabolism are exported by Mrp1 The
labile conjugates immediately disintegrate
after export to generate GSH
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
12 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 715
involves recycling of GSH (Fig 1) Thus the stimulated
GSH export is unlikely to compromise GSH-dependent
formaldehyde oxidation
Evidence for the role of formaldehyde in pathology
In healthy individuals the formaldehyde concentration in the
blood has been reported to be around 01 mM (Heck and
Casanova 2004) while that in the brain is about 02 mM
(hippocampus) and 04 mM (cortex) (Tong et al 2013a)
These levels of formaldehyde represent the normal phy-
siological balance between formaldehyde-generating and
formaldehyde-disposing processes However an increased
activity of formaldehyde-generating enzymes or an acute
exposure to high amounts of exogenous formaldehyde
without a concurrent elevation in the capacity to clear
formaldehyde will raise formaldehyde level in the body and
will lead to formaldehyde stress (He et al 2010) Indeed an
increased expressionactivity of the formaldehyde-generating
enzymes VAP1SSAO LSD1 and JHDM has been reported
for various diseases (Table 3) While a broad spectrum of
pathological conditions are associated with elevated levels of
VAP1SSAO an increase in the expression of the histone
demethylases has especially been observed in different types
of cancer (Table 3) The elevated expression of formalde-
hyde-generating enzymes is accompanied by increased
formaldehyde levels in diabetic rats (Tong et al 2013a) in
cancer tissue (Tong et al 2010) and in some human cancer
cell lines (Kato et al 2001 Tong et al 2010)
Increased expression of formaldehyde-generating enzymes
(Table 3) as well as elevated formaldehyde levels have also
been reported in brains of patients suffering from neurode-
generative diseases like Alzheimer rsquos disease (AD) or multi-
ple sclerosis (MS) (Khokhlov et al 1989 cited in Miao andHe 2012 Tong et al 2011 2013a) Some hypotheses have
been postulated that link the increase in formaldehyde level
to neuropathology For example some human subjects who
suffered from methanol poisoning developed symptoms of
MS which has been discussed to be an effect of methanol
oxidation to formaldehyde and the subsequent modi1047297cation
of proteins resulting in an immune reaction (Schwyzer and
Henzi 1983 Henzi 1984) Along that line it was discussed
that formaldehyde methylates proteins like tau (in AD) or
myelin basic protein (in MS) which in turn elicits an immune
response by the body that is characteristic for these diseases
(Monte 2010 Lu et al 2013) Also inhibition of SSAO in a
murine model of MS has been shown to reduce the incidence
and severity of this disease (Wang et al 2006) which could
at least partly be the consequence of a lowered formaldehyde
generation Moreover formaldehyde exposure has been
implicated to be a risk factor for the development of
amyotrophic lateral sclerosis (Weisskopf et al 2009) a
disease that is characterized by degeneration of motor
neurons (Kiernan et al 2011)
Formaldehyde-induced alterations in neuralmetabolism as potential contributors toneurodegeneration
Figure 3 summarizes the current knowledge on formalde-
hyde metabolism and on formaldehyde-induced alterations in
the glucose and GSH metabolism of neural cells The
potential of cultured brain cells to ef 1047297ciently metabolize
formaldehyde suggests that also the cells in brain deal quite
well with the moderate amounts of formaldehyde that are
generated under physiological conditions Similar to liver
cells brain cells are likely to use both cytosolic and
mitochondrial pathways for formaldehyde oxidation to
formate and further to carbon dioxide (Figs 1 and 3)
Cultured brain cells ef 1047297ciently produce and export glyco-
lytically generated lactate and also release GSH into the
medium although the basal rates of glycolysis and GSH
export differ between different types of neural cells (Tulpule
and Dringen 2011 2012 Tulpule et al 2012 2013) These
pathways are not affected by low concentrations of formal-
dehyde but as soon as formaldehyde levels are increased in
pathological conditions an accelerated generation of formate
is likely to stimulate glycolytic 1047298ux by inhibition of the
mitochondrial respiration (Fig 3) In addition an excess of
formaldehyde deprives brain cells of GSH by stimulating
Mrp1-mediated GSH export (Fig 3) Although caution should
be exercised while extrapolating in vitro data to the situation
in the brain a speculation on potential consequences of
Table 3 Elevation in expression or activity of formaldehyde-generat-
ing enzymes in human diseases
Enzyme Disease References
SSAOVAP1 Alzheimer rsquos disease Ferrer et al (2002) del Mar
Hernandez et al (2005)
Unzeta et al (2007)
Multiple sclerosis Airas et al (2006)
Heart disease Boomsma et al (2000 2005)
Diabetes mellitus
and diabetic
complications
Meszaros et al (1999)
Gr euroonvall-Nordquist
et al (2001) Karadi et al(2002) Boomsma et al
(2005) Obata (2006)
Chronic liver disease Kurkijarvi et al (2000)
LSD1JHDM Sarcoma Schildhaus et al (2011)
Bennani-Baiti et al (2012)
Peripheral nerve
sheath tumor
Schildhaus et al (2011)
Neuroblastoma Schulte et al (2009)
Bladder cancer Hayami et al (2010 2011)
Breast cancer Lim et al (2010)
Prost ate cancer Kahl et al (2006) Xiang
et al (2007)
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 13
7212019 Journal of Neurochemistry
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elevated formaldehyde levels in brain on the cellular metab-
olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of
cultured brain cells (01 ndash 1 mM) are in the concentration
range reported for the normal brain (02 ndash 04 mM) Thus mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig 4 Astrocytes and neurons in brain are likely to
ef 1047297ciently metabolize an excess of formaldehyde as also
reported for brain homogenates (Iborra et al 1992) Subse-
quently the formate generated from formaldehyde is either
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain
cells to at least transiently meet their energy demand
However prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al 2007) Besides this impairment of energy
metabolism formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003 Rose 2010) which would subsequently
induce astrocytic swelling impairment of neuronal signal
Fig 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the
generated formate is exported while a fraction is further oxidized to
carbon dioxide Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites
Fig 4 Potential consequences of an
excess of formaldehyde in brain Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed
indirect consequences (dark gray squares)
that 1047297nally lead to the adverse effects
reported for formaldehyde exposure
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
14 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 15
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Conflict of interest
The authors have no con1047298ict of interest to declare
References
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Biochem Biophys Res Commun 410 775 ndash 779
Li F Gong Q Dong H and Shi J (2012) Resveratrol a neuroprotective
supplement for Alzheimer rsquos disease Curr Pharm Des 18 27 ndash 33
Lim S Janzer A Becker A Zimmer A Schule R Buettner R and
Kirfel J (2010) Lysine-speci1047297c demethylase 1 (LSD1) is highly
expressed in ER-negative breast cancers and a biomarker
predicting aggressive biology Carcinogenesis 31 512 ndash 520
Lu S C (2013) Glutathione synthesis Biochim Biophys Acta 18303143 ndash 3153
Lu Z Li C M Qiao Y Yan Y and Yang X (2008) Effect of inhaled
formaldehyde on learning and memory of mice Indoor Air 18 77 ndash
83
Lu J Li C Su T Liu Y and He R (2013) Formaldehyde induces
hyperphosphorylation and polymerization of Tau protein both
in vitro and in vivo Biochim Biophys Acta 1830 4102 ndash 4116
Luo F C Zhou J Lv T Qi L Wang S D Nakamura H Yodoi J and
Bai J (2012) Induction of endoplasmic reticulum stress and the
modulation of thioredoxin-1 in formaldehyde-induced
neurotoxicity Neurotoxicology 33 290 ndash 298
Lushchak V I (2012) Glutathione homeostasis and functions potential
targets for medical interventions J Amino Acids 2012 736837
MacAllister S L Choi J Dedina L and OrsquoBrien P J (2011) Metabolic
mechanisms of methanolformaldehyde in isolated rat hepatocytes
Carbonyl-metabolizing enzymes versus oxidative stress Chem
Biol Interact 191 308 ndash 314
MacFarlane A J Perry C A Girnary H H Gao D Allen R H
Stabler S P Shane B and Stover P J (2009) Mthfd1 is anessential gene in mice and alters biomarkers of impaired one-
carbon metabolism J Biol Chem 284 1533 ndash 1539
Mahad D Ziabreva I Lassmann H and Turnbull D (2008)
Mitochondrial defects in acute multiple sclerosis lesions Brain
131 1722 ndash 1735
Malek F A Moritz K U and Fanghanel J (2003) A study on speci1047297c
behavioral effects of formaldehyde in the rat J Exp Anim Sci 42
160 ndash 170
del Mar Hernandez M Esteban M Szabo P Boada M and Unzeta M
(2005) Human plasma semicarbazide sensitive amine oxidase
(SSAO) b-amyloid protein and aging Neurosci Lett 384183 ndash 187
Martinez S E Vaglenova J Sabria J Martinez M C Farres J and
Pares X (2001) Distribution of alcohol dehydrogenase mRNA in
the rat central nervous system - consequences for brain ethanol and
retinoid metabolism Eur J Biochem 268 5045 ndash 5056Mason M J Mattsson K Pasternack M Voipio J and Kaila K (1990)
Postsynaptic fall in intracellular pH and increase in surface pH
caused by ef 1047298ux of formate and acetate anions through GABA-
gated channels in cray1047297sh muscle-1047297bers Neuroscience 34 359 ndash
368
Meinerz D F Comprasi B Allebrandt J et al (2013) Sub-acute
administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido)
succinate induces toxicity and oxidative stress in mice unexpected
effects of N-acetylcysteine Springerplus 2 182
Meszaros Z Szombathy T Raimondi L Karadi I Romics L and
Magyar K (1999) Elevated serum semicarbazide-sensitive amine
oxidase activity in non-insulin-dependent diabetes mellitus
correlation with body mass index and serum triglyceride
Metabolism 48 113 ndash 117
Metz B Kersten G F Hoogerhout P et al (2004) Identi1047297cation of formaldehyde-induced modi1047297cations in proteins reactions with
model peptides J Biol Chem 279 6235 ndash 6243
Metz B Kersten G F Baart G J de Jong A Meiring H ten Hove J
van Steenbergen M J Hennink W E Crommelin D J and
Jiskoot W (2006) Identi1047297cation of formaldehyde-induced
modi1047297cations in proteins reactions with insulin Bioconjug
Chem 17 815 ndash 822
Miao J and He R (2012) Chronic formaldehyde-mediated impairments
and age-related dementia in Neurodegeneration (Martin L M and
Loh S H Y eds) pp 59 ndash 76 InTech doi 10577234949
Monte W C (2010) Methanol a chemical Trojan horse as the root of the
inscrutable U Med Hypotheses 74 493 ndash 496
Moschen I Broer A Galic S Lang F and Broer S (2012) Signi1047297cance
of short chain fatty acid transport by members of the
monocarboxylate transporter family (MCT) Neurochem Res 372562 ndash 2568
Mukherjee S and Manahan-Vaughan D (2013) Role of metabotropic
glutamate receptors in persistent forms of hippocampal plasticity
and learning Neuropharmacology 66 65 ndash 81
Nazarian A Hermannsson B J Muller J Zurakowski D and Snyder
B D (2009) Effects of tissue preservation on murine bone
mechanical properties J Biomech 42 82 ndash 86
Neves A Costalat R and Pellerin L (2012) Determinants of brain
cell metabolic phenotypes and energy substrate utilization unraveled
with a modeling approach PLoS Comput Biol 8 e1002686
Neymeyer V Tephly T R and Miller M W (1997) Folate and 10-
formyltetrahydrofolate dehydrogenase (FDH) expression in the
central nervous system of the mature rat Brain Res 766 195 ndash 204
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
18 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1315
Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase
Biochem Biophys Res Commun 67 610 ndash 616
Nishimura M and Naito S (2006) Tissue-speci1047297c mRNA expression
pro1047297les of human phase I metabolizing enzymes except for
cytochrome P450 and phase II metabolizing enzymes Drug
Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
(SSAO) activity a review Life Sci 79 417 ndash 422
Obata T and Yamanaka Y (2000) Evidence for existence of
immobilization stress-inducible semicarbazide-sensitive amine
oxidase inhibitor in rat brain cytosol Neurosci Lett 296 58 ndash 60
Oldham M C Konopka G Iwamoto K Langfelder P Kato T
Horvath S and Geschwind D (2008) Functional organization of
the transcriptome in the human brain Nat Neurosci 11 1271 ndash
1282
Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide
diversity of function and pharmacology Neuropharmacology 56
141 ndash 148
OrsquoSullivan J Unzeta M Healy J OrsquoSullivan M I Davey G and
Tipton K F (2004) Semicarbazide-sensitive amine oxidases
enzymes with quite a lot to do Neurotoxicology 25 303 ndash 315Oyama Y Sakai H Arata T Okano Y Akaike N Sakai K and Noda
K (2002) Cytotoxic effects of methanol formaldehyde and
formate on dissociated rat thymocytes a possibility of aspartame
toxicity Cell Biol Toxicol 18 43 ndash 50
Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D
(2011) Energy failure in multiple sclerosis and its investigation
using MR techniques J Neurol 258 2113 ndash 2127
Parnetti L Reboldi G P and Gallai V (2000) Cerebrospinal 1047298uid
pyruvate levels in Alzheimer rsquos disease and vascular dementia
Neurology 54 735 ndash 737
Pauwels P J Opperdoes F R and Trouet A (1985) Effects of
antimycin glucose deprivation and serum on cultures of neurons
astrocytes and neuroblastoma cells J Neurochem 44 143 ndash 148
Pitten F A Kramer A Herrmann K Breme I and Koch S (2000)
Formaldehyde neurotoxicity in animal experiments Pathol ResPract 196 193 ndash 198
Prasannan P Pike S Peng K Shane B and Appling D R (2003)
Human mitochondrial C1-tetrahydrofolate synthase gene structure
tissue distribution of the mRNA and immunolocalization in
Chinese hamster ovary cells J Biol Chem 278 43178 ndash 43187
Regan R F and Guo Y P (1999a) Extracellular reduced glutathione
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glucose deprivation Brain Res 817 145 ndash 150
Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
high concentrations of extracellular reduced glutathione
Neuroscience 91 463 ndash 470
Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
Merillon J M and Monti J P (2011) Neuroprotective properties
of resveratrol and derivatives Ann N Y Acad Sci 1215 103 ndash
108Rose C F (2010) Increase brain lactate in hepatic encephalopathy cause
or consequence Neurochem Int 57 389 ndash 394
Ross J M Oberg J Brene S et al (2010) High brain lactate is a
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dehydrogenase AB ratio Proc Natl Acad Sci USA 107
20087 ndash 20092
Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
indoor environment Chem Rev 110 2536 ndash 2572
Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
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formaldehyde exposure on pyramidal cell number volume of cell
layer in hippocampus and hemisphere in the rat a stereological
study Brain Res 1145 157 ndash 167
Sasseville D (2004) Hypersensitivity to preservatives Dermatol Ther
17 251 ndash 263
Schad A Fahimi H D Volkl A and Baumgart E (2003) Expression
of catalase mRNA and protein in adult rat brain detectionby nonradioactive in situ hybridization with signal ampli1047297cation
by catalyzed reporter deposition (ISH-CAR D) and
immunohistochemistry (IHC)immuno1047298uorescence (IF) J
Histochem Cytochem 51 751 ndash 760
Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux
in cultured astrocytes Neurochem Res 36 894 ndash 903
Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c
demethylase 1 is highly expressed in solitary 1047297brous tumors
synovial sarcomas rhabdomyosarcomas desmoplastic small round
cell tumors and malignant peripheral nerve sheath tumors Hum
Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
1029 ndash 1050 Neural Metabolism in vivo Springer New York
Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
neuroblastoma implications for therapy Cancer Res 69 2065 ndash
2071
Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
by 2-step demyelination Med Hypotheses 12 129 ndash 142
Skrzydlewska E (2003) Toxicological and metabolic consequences of
methanol poisoning Toxicol Mech Methods 13 277 ndash 293
Smith D J and Vainio P J (2007) Targeting vascular adhesion protein-
1 to treat autoimmune and in1047298ammatory diseases Ann N Y Acad
Sci 1110 382 ndash 388
Sohal R S and Orr W C (2012) The redox stress hypothesis of aging
Free Radic Biol Med 52 539 ndash 555
Song M S Baker G B Dursun S M and Todd K G (2010) The
antidepressant phenelzine protects neurons and astrocytes
against formaldehyde-induced toxicity J Neurochem 1141405 ndash 1413
Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
Ilhan N (2008) The effects of inhaled formaldehyde on oxidant and
antioxidant systems of rat cerebellum during the postnatal
development process Toxicol Mech Methods 18 569 ndash 574
Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
formaldehyde on the nervous system Rev Environ Contam
Toxicol 203 105 ndash 118
Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
formaldehyde exposure produces enhanced fear conditioning to
odor in male but not female rats Brain Res 1008 11 ndash 19
Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
(2009) The janus face of alcohol dehydrogenase 3 Chem Biol
Interact 178 29 ndash 35
Staub F Peters J Kempski O Schneider G H Schurer Land Baethmann A (1993) Swelling of glial cells in lactacidosis
and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash
74
Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
less support implications for Alzheimer rsquos disease Neurobiol
Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
P Cuenod M and Do K Q (2010) Redox dysregulation affects
the ventral but not dorsal hippocampus impairment of
parvalbumin neurons gamma oscillations and related behaviors
J Neurosci 30 2547 ndash 2558
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Formaldehyde in brain 19
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1415
Stewart M J Malek K and Crabb D W (1996) Distribution of
messenger RNAs for aldehyde dehydrogenase 1 aldehyde
dehydrogenase 2 and aldehyde dehydrogenase 5 in human
tissues J Investig Med 44 42 ndash 46
Sullivan P G and Brown M R (2005) Mitochondrial aging and
dysfunction in Alzheimer rsquos disease Prog Neuropsychopharmacol
Biol Psychiatry 29 407 ndash 410
Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
Magistretti P J and Alberini C M (2011) Astrocyte-neuron
lactate transport is required for long-term memory formation Cell
144 810 ndash 823
Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
and health effects Environ Int 35 1210 ndash 1224
Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
neurotoxicity to PC12 cells involving inhibition of paraoxonase-1
expression and activity Clin Exp Pharmacol Physiol 38 208 ndash
214
Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
1041
Thigpen A E West M G and Appling D R (1990) Rat C1-
tetrahydrofolate synthase cDNA isolation tissue-speci1047297c levels of
the mRNA and expression of the protein in yeast J Biol Chem
265 7907 ndash 7913
Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
dehydrogenase beyond phase I metabolism Toxicol Lett 193
1 ndash 3
Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev
Nutr 30 57 ndash 81
Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
formaldehyde and acidic microenvironment synergistically induce
bone cancer pain PLoS ONE 5 e10234
Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
inversely correlated to mini mental state examination scores in
senile dementia Neurobiol Aging 32 31 ndash 41
Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
R (2013a) Accumulated hippocampal formaldehyde induces age-
dependent memory decline Age (Dordr) 35 583 ndash 596
Tong Z Han C Luo W et al (2013b) Aging-associated excess
formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635
Tulpule K and Dringen R (2012) Formate generated by cellular
oxidation of formaldehyde accelerates the glycolytic 1047298ux in
cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
Neurochem Int 61 1302 ndash 1313
Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
metabolism and formaldehyde-induced stimulation of lactate
production and glutathione export in cultured neurons
J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
performance study Erciyes Med J 30 211 ndash 217
Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74
Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
vasculature pathological synergy of Alzheimer rsquos disease and
diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
(1997) Mitochondria-mediated cell injury Symposium overview
Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
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involves recycling of GSH (Fig 1) Thus the stimulated
GSH export is unlikely to compromise GSH-dependent
formaldehyde oxidation
Evidence for the role of formaldehyde in pathology
In healthy individuals the formaldehyde concentration in the
blood has been reported to be around 01 mM (Heck and
Casanova 2004) while that in the brain is about 02 mM
(hippocampus) and 04 mM (cortex) (Tong et al 2013a)
These levels of formaldehyde represent the normal phy-
siological balance between formaldehyde-generating and
formaldehyde-disposing processes However an increased
activity of formaldehyde-generating enzymes or an acute
exposure to high amounts of exogenous formaldehyde
without a concurrent elevation in the capacity to clear
formaldehyde will raise formaldehyde level in the body and
will lead to formaldehyde stress (He et al 2010) Indeed an
increased expressionactivity of the formaldehyde-generating
enzymes VAP1SSAO LSD1 and JHDM has been reported
for various diseases (Table 3) While a broad spectrum of
pathological conditions are associated with elevated levels of
VAP1SSAO an increase in the expression of the histone
demethylases has especially been observed in different types
of cancer (Table 3) The elevated expression of formalde-
hyde-generating enzymes is accompanied by increased
formaldehyde levels in diabetic rats (Tong et al 2013a) in
cancer tissue (Tong et al 2010) and in some human cancer
cell lines (Kato et al 2001 Tong et al 2010)
Increased expression of formaldehyde-generating enzymes
(Table 3) as well as elevated formaldehyde levels have also
been reported in brains of patients suffering from neurode-
generative diseases like Alzheimer rsquos disease (AD) or multi-
ple sclerosis (MS) (Khokhlov et al 1989 cited in Miao andHe 2012 Tong et al 2011 2013a) Some hypotheses have
been postulated that link the increase in formaldehyde level
to neuropathology For example some human subjects who
suffered from methanol poisoning developed symptoms of
MS which has been discussed to be an effect of methanol
oxidation to formaldehyde and the subsequent modi1047297cation
of proteins resulting in an immune reaction (Schwyzer and
Henzi 1983 Henzi 1984) Along that line it was discussed
that formaldehyde methylates proteins like tau (in AD) or
myelin basic protein (in MS) which in turn elicits an immune
response by the body that is characteristic for these diseases
(Monte 2010 Lu et al 2013) Also inhibition of SSAO in a
murine model of MS has been shown to reduce the incidence
and severity of this disease (Wang et al 2006) which could
at least partly be the consequence of a lowered formaldehyde
generation Moreover formaldehyde exposure has been
implicated to be a risk factor for the development of
amyotrophic lateral sclerosis (Weisskopf et al 2009) a
disease that is characterized by degeneration of motor
neurons (Kiernan et al 2011)
Formaldehyde-induced alterations in neuralmetabolism as potential contributors toneurodegeneration
Figure 3 summarizes the current knowledge on formalde-
hyde metabolism and on formaldehyde-induced alterations in
the glucose and GSH metabolism of neural cells The
potential of cultured brain cells to ef 1047297ciently metabolize
formaldehyde suggests that also the cells in brain deal quite
well with the moderate amounts of formaldehyde that are
generated under physiological conditions Similar to liver
cells brain cells are likely to use both cytosolic and
mitochondrial pathways for formaldehyde oxidation to
formate and further to carbon dioxide (Figs 1 and 3)
Cultured brain cells ef 1047297ciently produce and export glyco-
lytically generated lactate and also release GSH into the
medium although the basal rates of glycolysis and GSH
export differ between different types of neural cells (Tulpule
and Dringen 2011 2012 Tulpule et al 2012 2013) These
pathways are not affected by low concentrations of formal-
dehyde but as soon as formaldehyde levels are increased in
pathological conditions an accelerated generation of formate
is likely to stimulate glycolytic 1047298ux by inhibition of the
mitochondrial respiration (Fig 3) In addition an excess of
formaldehyde deprives brain cells of GSH by stimulating
Mrp1-mediated GSH export (Fig 3) Although caution should
be exercised while extrapolating in vitro data to the situation
in the brain a speculation on potential consequences of
Table 3 Elevation in expression or activity of formaldehyde-generat-
ing enzymes in human diseases
Enzyme Disease References
SSAOVAP1 Alzheimer rsquos disease Ferrer et al (2002) del Mar
Hernandez et al (2005)
Unzeta et al (2007)
Multiple sclerosis Airas et al (2006)
Heart disease Boomsma et al (2000 2005)
Diabetes mellitus
and diabetic
complications
Meszaros et al (1999)
Gr euroonvall-Nordquist
et al (2001) Karadi et al(2002) Boomsma et al
(2005) Obata (2006)
Chronic liver disease Kurkijarvi et al (2000)
LSD1JHDM Sarcoma Schildhaus et al (2011)
Bennani-Baiti et al (2012)
Peripheral nerve
sheath tumor
Schildhaus et al (2011)
Neuroblastoma Schulte et al (2009)
Bladder cancer Hayami et al (2010 2011)
Breast cancer Lim et al (2010)
Prost ate cancer Kahl et al (2006) Xiang
et al (2007)
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 13
7212019 Journal of Neurochemistry
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elevated formaldehyde levels in brain on the cellular metab-
olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of
cultured brain cells (01 ndash 1 mM) are in the concentration
range reported for the normal brain (02 ndash 04 mM) Thus mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig 4 Astrocytes and neurons in brain are likely to
ef 1047297ciently metabolize an excess of formaldehyde as also
reported for brain homogenates (Iborra et al 1992) Subse-
quently the formate generated from formaldehyde is either
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain
cells to at least transiently meet their energy demand
However prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al 2007) Besides this impairment of energy
metabolism formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003 Rose 2010) which would subsequently
induce astrocytic swelling impairment of neuronal signal
Fig 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the
generated formate is exported while a fraction is further oxidized to
carbon dioxide Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites
Fig 4 Potential consequences of an
excess of formaldehyde in brain Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed
indirect consequences (dark gray squares)
that 1047297nally lead to the adverse effects
reported for formaldehyde exposure
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
14 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 15
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1015
Conflict of interest
The authors have no con1047298ict of interest to declare
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Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
high concentrations of extracellular reduced glutathione
Neuroscience 91 463 ndash 470
Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
Merillon J M and Monti J P (2011) Neuroprotective properties
of resveratrol and derivatives Ann N Y Acad Sci 1215 103 ndash
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hallmark of aging and caused by a shift in the lactate
dehydrogenase AB ratio Proc Natl Acad Sci USA 107
20087 ndash 20092
Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
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Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
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Sasseville D (2004) Hypersensitivity to preservatives Dermatol Ther
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of catalase mRNA and protein in adult rat brain detectionby nonradioactive in situ hybridization with signal ampli1047297cation
by catalyzed reporter deposition (ISH-CAR D) and
immunohistochemistry (IHC)immuno1047298uorescence (IF) J
Histochem Cytochem 51 751 ndash 760
Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux
in cultured astrocytes Neurochem Res 36 894 ndash 903
Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c
demethylase 1 is highly expressed in solitary 1047297brous tumors
synovial sarcomas rhabdomyosarcomas desmoplastic small round
cell tumors and malignant peripheral nerve sheath tumors Hum
Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
1029 ndash 1050 Neural Metabolism in vivo Springer New York
Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
neuroblastoma implications for therapy Cancer Res 69 2065 ndash
2071
Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
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Free Radic Biol Med 52 539 ndash 555
Song M S Baker G B Dursun S M and Todd K G (2010) The
antidepressant phenelzine protects neurons and astrocytes
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Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
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Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
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Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
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J Neurosci 30 2547 ndash 2558
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7212019 Journal of Neurochemistry
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Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
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20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
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elevated formaldehyde levels in brain on the cellular metab-
olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of
cultured brain cells (01 ndash 1 mM) are in the concentration
range reported for the normal brain (02 ndash 04 mM) Thus mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig 4 Astrocytes and neurons in brain are likely to
ef 1047297ciently metabolize an excess of formaldehyde as also
reported for brain homogenates (Iborra et al 1992) Subse-
quently the formate generated from formaldehyde is either
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain
cells to at least transiently meet their energy demand
However prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al 2007) Besides this impairment of energy
metabolism formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003 Rose 2010) which would subsequently
induce astrocytic swelling impairment of neuronal signal
Fig 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the
generated formate is exported while a fraction is further oxidized to
carbon dioxide Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites
Fig 4 Potential consequences of an
excess of formaldehyde in brain Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed
indirect consequences (dark gray squares)
that 1047297nally lead to the adverse effects
reported for formaldehyde exposure
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14 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 15
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Conflict of interest
The authors have no con1047298ict of interest to declare
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formaldehyde contact allergy Part 2 Patch test relationship
to formaldehyde contact allergy experimental provocationtests amount of formaldehyde released and assessment of risk
to consumers allergic to formaldehyde Contact Derm 62
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Halim N D McFate T Mohyeldin A et al (2010) Phosphorylation
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Harris C Wang S W Lauchu J J and Hansen J M (2003) Methanol
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Hayami S Kelly J D Cho H S et al (2011) Overexpression of LSD1
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Herrero-Mendez A Almeida A Fernandez E Maestre C Moncada S
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Janaky R Cruz-Aguado R Oja S S and Shaw C A (2007)
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recurrence Cancer Res 66 11341 ndash 11347
Kapur B M Vandenbroucke A C Adamchik Y Lehotay D C and
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Karadi I Meszaros Z Csanyi A Szombathy T Hosszufalusi N
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Formaldehyde in human cancer cells detection by preconcentration-
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Keppler D (2011) Multidrug resistance proteins (MRPs ABCCs)
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Kurkijarvi R Yegutkin G G Gunson B K Jalkanen S Salmi M and
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Laitinen J Makela M Mikkola J and Huttu I (2010) Fire 1047297ghting
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Lee E S Chen H Hardman C Simm A and Charlton C (2008)
Excessive S-adenosyl-L-methionine-dependent methylation
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Lewerenz J Dargusch R and Maher P (2010) Lactacidosis modulates
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Li F Liu X Su Z and Sun R (2011) Acidosis leads to brain
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Li F Gong Q Dong H and Shi J (2012) Resveratrol a neuroprotective
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Lim S Janzer A Becker A Zimmer A Schule R Buettner R and
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Lu S C (2013) Glutathione synthesis Biochim Biophys Acta 18303143 ndash 3153
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Lu J Li C Su T Liu Y and He R (2013) Formaldehyde induces
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Luo F C Zhou J Lv T Qi L Wang S D Nakamura H Yodoi J and
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Lushchak V I (2012) Glutathione homeostasis and functions potential
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MacAllister S L Choi J Dedina L and OrsquoBrien P J (2011) Metabolic
mechanisms of methanolformaldehyde in isolated rat hepatocytes
Carbonyl-metabolizing enzymes versus oxidative stress Chem
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Mahad D Ziabreva I Lassmann H and Turnbull D (2008)
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Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
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Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
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Formaldehyde in brain 19
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Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
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Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
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Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
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Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
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Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
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Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
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20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
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7212019 Journal of Neurochemistry
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transmission and neurological de1047297cits (Staub et al 1993 Li
et al 2011 Zhao et al 2011)
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive
oxygen species and detoxi1047297cation of xenobiotics (Lushchak
2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al 2006 2007 2011 Songur et al 2008) A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis However lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis
(Lewerenz et al 2010) and cellular GSH levels are likely to
remain low Thus chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al 2007) which play impor-
tant roles in memory and learning (Davis et al 2013
Mukherjee and Manahan-Vaughan 2013) Also accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt
and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a b)
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure Acute exposure of neural cells to formaldehyde
andor the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig 4
light gray squares) which may subsequently lead to indirect
delayed consequences (Fig 4 dark gray squares) Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure such as acceler-
ated glycolysis or GSH export to the known adverse effects
of formaldehyde on neural cells (Table 2) Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde
For example formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al 2011 Luo et al 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2 while the expression of pro-
apoptotic Bax protein increases (Tang et al 2012) Also the
expression of the rate-limiting enzyme in dopamine synthesis
tyrosine hydroxylase is lowered in PC12 cells after exposure
to formaldehyde (Lee et al 2008) Further studies are now
required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al 1989 cited in Miao and He 2012
Tong et al 2011 2013a b) show impaired mitochondrial
function (Sullivan and Brown 2005 Mahad et al 2008
Boumezbeur et al 2010 Leuner et al 2012) together with
an increase in brain lactate content (Parnetti et al 2000 Ross
et al 2010 Paling et al 2011) Moreover ageing MS and
AD have been connected with oxidative stress in the brain
(Haider et al 2011 van Horssen et al 2011 Belkacemi
and Ramassamy 2012 Sohal and Orr 2012 Steele and
Robinson 2012) These reports strengthen the view that
formaldehyde may at least to some extent have a role in the
initiation andor progression of pathological symptoms of
neurodegenerative conditions (Yu 2001 Monte 2010) An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al 2011) while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al 2010) Thus the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the de1047297cits in behavior cognition and
learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al
2011 2013a b)
Conclusions and future perspectives
In conclusion elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress a direct causal link between
formaldehyde impaired metabolism and oxidative stress
remains to be demonstrated Interestingly resveratrol which
is known to be neuroprotective for AD (Richard et al 2011
Li et al 2012) is a formaldehyde scavenger (Tyihak and
Kir aly-Veghely 2008) suggesting that the bene1047297cial effects
of resveratrol could also include removal of excess formal-
dehyde Further studies that will combine the quanti1047297cation
of formaldehyde levels in post-mortem brains with metab-
olite pro1047297les and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 15
7212019 Journal of Neurochemistry
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Conflict of interest
The authors have no con1047298ict of interest to declare
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Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
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Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide
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Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D
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Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
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Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
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Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
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Pathol 42 1667 ndash 1675
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in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
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2071
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Song M S Baker G B Dursun S M and Todd K G (2010) The
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Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
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Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
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Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
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Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
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Interact 178 29 ndash 35
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74
Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
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Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
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parvalbumin neurons gamma oscillations and related behaviors
J Neurosci 30 2547 ndash 2558
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Formaldehyde in brain 19
7212019 Journal of Neurochemistry
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Stewart M J Malek K and Crabb D W (1996) Distribution of
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Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
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Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
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Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
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attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
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Thigpen A E West M G and Appling D R (1990) Rat C1-
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Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
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1 ndash 3
Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev
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Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
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Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
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formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635
Tulpule K and Dringen R (2012) Formate generated by cellular
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Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
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Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
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Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
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Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
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diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
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Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1015
Conflict of interest
The authors have no con1047298ict of interest to declare
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7212019 Journal of Neurochemistry
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van Horssen J Witte M E Schreibelt G and de Vries H E (2011)
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Karadi I Meszaros Z Csanyi A Szombathy T Hosszufalusi N
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Kato S Burke P J Koch T H and Bierbaum V M (2001)
Formaldehyde in human cancer cells detection by preconcentration-
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Keppler D (2011) Multidrug resistance proteins (MRPs ABCCs)
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Kiernan J A (2000) Formaldehyde formalin paraformaldehyde and
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Kiernan M C Vucic S Cheah B C Turner M R Eisen A Hardiman
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Kurkijarvi R Yegutkin G G Gunson B K Jalkanen S Salmi M and
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Laitinen J Makela M Mikkola J and Huttu I (2010) Fire 1047297ghting
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Lee E S Chen H Hardman C Simm A and Charlton C (2008)
Excessive S-adenosyl-L-methionine-dependent methylation
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Lee M Schwab C and McGeer P L (2011) Astrocytes are GABAergic
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Leuner K Muller W E and Reichert A S (2012) From mitochondrial
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Lewerenz J Dargusch R and Maher P (2010) Lactacidosis modulates
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Li F Liu X Su Z and Sun R (2011) Acidosis leads to brain
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Li F Gong Q Dong H and Shi J (2012) Resveratrol a neuroprotective
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Lim S Janzer A Becker A Zimmer A Schule R Buettner R and
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Lu S C (2013) Glutathione synthesis Biochim Biophys Acta 18303143 ndash 3153
Lu Z Li C M Qiao Y Yan Y and Yang X (2008) Effect of inhaled
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Lu J Li C Su T Liu Y and He R (2013) Formaldehyde induces
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Luo F C Zhou J Lv T Qi L Wang S D Nakamura H Yodoi J and
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neurotoxicity Neurotoxicology 33 290 ndash 298
Lushchak V I (2012) Glutathione homeostasis and functions potential
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MacAllister S L Choi J Dedina L and OrsquoBrien P J (2011) Metabolic
mechanisms of methanolformaldehyde in isolated rat hepatocytes
Carbonyl-metabolizing enzymes versus oxidative stress Chem
Biol Interact 191 308 ndash 314
MacFarlane A J Perry C A Girnary H H Gao D Allen R H
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Metz B Kersten G F Hoogerhout P et al (2004) Identi1047297cation of formaldehyde-induced modi1047297cations in proteins reactions with
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Metz B Kersten G F Baart G J de Jong A Meiring H ten Hove J
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Miao J and He R (2012) Chronic formaldehyde-mediated impairments
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Neymeyer V Tephly T R and Miller M W (1997) Folate and 10-
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Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
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Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
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Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
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Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
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Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
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Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
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Formaldehyde in brain 19
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Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
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Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
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Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
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Formaldehyde in brain 21
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Gr euroonvall-Nordquist J L Backlund L B Garpenstrand H Ekblom J
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de Groot A White I R Flyvholm M A Lensen G and Coenraads P
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formaldehyde contact allergy Part 2 Patch test relationship
to formaldehyde contact allergy experimental provocationtests amount of formaldehyde released and assessment of risk
to consumers allergic to formaldehyde Contact Derm 62
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Guo J M Liu A J Zang P et al (2013) ALDH2 protects against
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Gurel A Coskun O Armutcu F Kante M and Ozen O A (2005)
Vitamin E against oxidative damage caused by formaldehyde in
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Haider L Fischer M T Frischer J M Bauer J Hoftberger R Botond
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Halim N D McFate T Mohyeldin A et al (2010) Phosphorylation
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Harris C Wang S W Lauchu J J and Hansen J M (2003) Methanol
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Hayami S Kelly J D Cho H S et al (2011) Overexpression of LSD1
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Heck H D and Casanova M (2004) The implausibility of leukemia
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Heck H D Casanova-Schmitz M Dodd P B Schachter E N Witek
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the blood of humans and Fischer-344 rats exposed to CH2O under
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Heck H D Casanova M and Starr T B (1990) Formaldehyde toxicity -
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Hedberg J J Backlund M Stromberg P Lonn S Dahl M L
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Pharmacogenetics 11 815 ndash 824
Henzi H (1984) Chronic methanol poisoning with the clinical and
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Herrero-Mendez A Almeida A Fernandez E Maestre C Moncada S
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enzyme by APCC ndash Cdh1 Nat Cell Biol 11 747 ndash 752
van Horssen J Schreibelt G Drexhage J Hazes T Dijkshtra C D
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damage in multiple sclerosis lesions coincides with enhanced
antioxidant enzyme expression Free Radic Biol Med 45 1729 ndash
1737
van Horssen J Witte M E Schreibelt G and de Vries H E (2011)
Radical changes in multiple sclerosis pathogenesis Biochim
Biophys Acta 1812 141 ndash 150
Hou H and Yu H (2010) Structural insights into histone lysine
demethylation Curr Opin Struct Biol 20 739 ndash 748
Iborra F J Renau-Piqueras J Portoles M Boleda M D Guerri C and
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dehydrogenase) in the nucleus J Histochem Cytochem 40 1865 ndash
1878
Izzo A and Schneider R (2010) Chatting histone modi1047297cations in
mammals Brief Funct Genomics 9 429 ndash 443
Jalkanen S and Salmi M (2001) Cell surface monoamine oxidases
enzymes in search of a function EMBO J 20 3893 ndash 3901
Jalkanen S and Salmi M (2008) VAP-1 and CD73 endothelial cell
surface enzymes in leukocyte extravasation Arterioscler Thromb
Vasc Biol 28 18 ndash 26
Janaky R Cruz-Aguado R Oja S S and Shaw C A (2007)
Glutathione in the nervous system roles in neural function and
health and implications for neurological disease in Handbook of
Neurochemistry (Oja S S Schousboe A and Saransaari P eds)
pp 347 ndash 399 Amino Acids and Peptides in the Nervous SystemSpringer Heidelberg
Julia P Farres J and Pares X (1987) Characterization of three
isoenzymes of rat alcohol-dehydrogenase - tissue distribution
and physical and enzymatic-properties Eur J Biochem 162
179 ndash 189
Kahl P Gullotti L Heukamp L C et al (2006) Androgen receptor
coactivators lysine-speci1047297c histone demethylase 1 and four and a
half LIM domain protein 2 predict risk of prostate cancer
recurrence Cancer Res 66 11341 ndash 11347
Kapur B M Vandenbroucke A C Adamchik Y Lehotay D C and
Carlen P L (2007) Formic acid a novel metabolite of chronic
ethanol abuse causes neurotoxicity which is prevented by folic
acid Alcohol Clin Exp Res 31 2114 ndash 2120
Karadi I Meszaros Z Csanyi A Szombathy T Hosszufalusi N
Romics L and Magyar K (2002) Serum semicarbazide-sensitiveamine oxidase (SSAO) activity is an independent marker of carotid
atherosclerosis Clin Chim Acta 323 139 ndash 146
Kato S Burke P J Koch T H and Bierbaum V M (2001)
Formaldehyde in human cancer cells detection by preconcentration-
chemical ionization mass spectrometry Anal Chem 73 2992 ndash
2997
Keppler D (2011) Multidrug resistance proteins (MRPs ABCCs)
importance for pathophysiology and drug therapy Handb Exp
Pharmacol 201 299 ndash 323
Khokhlov A P Zavalishin I A Savchenko I N and Dziuba A N
(1989) Disorders of formaldehyde metabolism and its metabolic
precursors in patients with multiple sclerosis Zh Nevropatol
Psikhiatr Im S S Korsakova 89 45 ndash 48
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 17
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1215
Kiernan J A (2000) Formaldehyde formalin paraformaldehyde and
glutaraldehyde what they are and what they do Microsc Today 1
8 ndash 12
Kiernan M C Vucic S Cheah B C Turner M R Eisen A Hardiman
O Burrell J R and Zoing M C (2011) Amyotrophic lateral
sclerosis Lancet 377 942 ndash 955Kilburn K H Seidman B C and Warshaw R (1985a) Neurobehavioral
and respiratory symptoms of formaldehyde and xylene exposure in
histology technicians Arch Environ Health 40 229 ndash 233
Kilburn K H Warshaw R Boylen C T Johnson S J Seidman B
Sinclair R and Takaro T Jr (1985b) Pulmonary and
neurobehavioral effects of formaldehyde exposure Arch
Environ Health 40 254 ndash 260
Krupenko S A (2009) FDH an aldehyde dehydrogenase fusion enzyme
in folate metabolism Chem Biol Interact 178 84 ndash 93
Krupenko N I Dubard M E Strickland K C Moxley K M Oleinik
N V and Krupenko S A (2010) ALDH1L2 is the mitochondrial
homolog of 10-formyltetrahydrofolate dehydrogenase J Biol
Chem 285 23056 ndash 23063
Kurkijarvi R Yegutkin G G Gunson B K Jalkanen S Salmi M and
Adams D H (2000) Circulating soluble vascular adhesion protein1 accounts for the increased serum monoamine oxidase activity in
chronic liver disease Gastroenterology 119 1096 ndash 1103
Laitinen J Makela M Mikkola J and Huttu I (2010) Fire 1047297ghting
trainersrsquo exposure to carcinogenic agents in smoke diving
simulators Toxicol Lett 192 61 ndash 65
Lee E S Chen H Hardman C Simm A and Charlton C (2008)
Excessive S-adenosyl-L-methionine-dependent methylation
increases levels of methanol formaldehyde and formic acid in rat
brain striatal homogenates possible role in S-adenosyl-
L-methionine-induced Parkinsonrsquos disease-like disorders Life
Sci 83 821 ndash 827
Lee M Schwab C and McGeer P L (2011) Astrocytes are GABAergic
cells that modulate microglial activity Glia 59 152 ndash 165
Leuner K Muller W E and Reichert A S (2012) From mitochondrial
dysfunction to amyloid beta formation novel insights into thepathogenesis of Alzheimer rsquos disease Mol Neurobiol 46 186 ndash
193
Lewerenz J Dargusch R and Maher P (2010) Lactacidosis modulates
glutathione metabolism and oxidative glutamate toxicity
J Neurochem 113 502 ndash 514
Li F Liu X Su Z and Sun R (2011) Acidosis leads to brain
dysfunctions through impairing cortical GABAergic neurons
Biochem Biophys Res Commun 410 775 ndash 779
Li F Gong Q Dong H and Shi J (2012) Resveratrol a neuroprotective
supplement for Alzheimer rsquos disease Curr Pharm Des 18 27 ndash 33
Lim S Janzer A Becker A Zimmer A Schule R Buettner R and
Kirfel J (2010) Lysine-speci1047297c demethylase 1 (LSD1) is highly
expressed in ER-negative breast cancers and a biomarker
predicting aggressive biology Carcinogenesis 31 512 ndash 520
Lu S C (2013) Glutathione synthesis Biochim Biophys Acta 18303143 ndash 3153
Lu Z Li C M Qiao Y Yan Y and Yang X (2008) Effect of inhaled
formaldehyde on learning and memory of mice Indoor Air 18 77 ndash
83
Lu J Li C Su T Liu Y and He R (2013) Formaldehyde induces
hyperphosphorylation and polymerization of Tau protein both
in vitro and in vivo Biochim Biophys Acta 1830 4102 ndash 4116
Luo F C Zhou J Lv T Qi L Wang S D Nakamura H Yodoi J and
Bai J (2012) Induction of endoplasmic reticulum stress and the
modulation of thioredoxin-1 in formaldehyde-induced
neurotoxicity Neurotoxicology 33 290 ndash 298
Lushchak V I (2012) Glutathione homeostasis and functions potential
targets for medical interventions J Amino Acids 2012 736837
MacAllister S L Choi J Dedina L and OrsquoBrien P J (2011) Metabolic
mechanisms of methanolformaldehyde in isolated rat hepatocytes
Carbonyl-metabolizing enzymes versus oxidative stress Chem
Biol Interact 191 308 ndash 314
MacFarlane A J Perry C A Girnary H H Gao D Allen R H
Stabler S P Shane B and Stover P J (2009) Mthfd1 is anessential gene in mice and alters biomarkers of impaired one-
carbon metabolism J Biol Chem 284 1533 ndash 1539
Mahad D Ziabreva I Lassmann H and Turnbull D (2008)
Mitochondrial defects in acute multiple sclerosis lesions Brain
131 1722 ndash 1735
Malek F A Moritz K U and Fanghanel J (2003) A study on speci1047297c
behavioral effects of formaldehyde in the rat J Exp Anim Sci 42
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del Mar Hernandez M Esteban M Szabo P Boada M and Unzeta M
(2005) Human plasma semicarbazide sensitive amine oxidase
(SSAO) b-amyloid protein and aging Neurosci Lett 384183 ndash 187
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the rat central nervous system - consequences for brain ethanol and
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Postsynaptic fall in intracellular pH and increase in surface pH
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Meinerz D F Comprasi B Allebrandt J et al (2013) Sub-acute
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effects of N-acetylcysteine Springerplus 2 182
Meszaros Z Szombathy T Raimondi L Karadi I Romics L and
Magyar K (1999) Elevated serum semicarbazide-sensitive amine
oxidase activity in non-insulin-dependent diabetes mellitus
correlation with body mass index and serum triglyceride
Metabolism 48 113 ndash 117
Metz B Kersten G F Hoogerhout P et al (2004) Identi1047297cation of formaldehyde-induced modi1047297cations in proteins reactions with
model peptides J Biol Chem 279 6235 ndash 6243
Metz B Kersten G F Baart G J de Jong A Meiring H ten Hove J
van Steenbergen M J Hennink W E Crommelin D J and
Jiskoot W (2006) Identi1047297cation of formaldehyde-induced
modi1047297cations in proteins reactions with insulin Bioconjug
Chem 17 815 ndash 822
Miao J and He R (2012) Chronic formaldehyde-mediated impairments
and age-related dementia in Neurodegeneration (Martin L M and
Loh S H Y eds) pp 59 ndash 76 InTech doi 10577234949
Monte W C (2010) Methanol a chemical Trojan horse as the root of the
inscrutable U Med Hypotheses 74 493 ndash 496
Moschen I Broer A Galic S Lang F and Broer S (2012) Signi1047297cance
of short chain fatty acid transport by members of the
monocarboxylate transporter family (MCT) Neurochem Res 372562 ndash 2568
Mukherjee S and Manahan-Vaughan D (2013) Role of metabotropic
glutamate receptors in persistent forms of hippocampal plasticity
and learning Neuropharmacology 66 65 ndash 81
Nazarian A Hermannsson B J Muller J Zurakowski D and Snyder
B D (2009) Effects of tissue preservation on murine bone
mechanical properties J Biomech 42 82 ndash 86
Neves A Costalat R and Pellerin L (2012) Determinants of brain
cell metabolic phenotypes and energy substrate utilization unraveled
with a modeling approach PLoS Comput Biol 8 e1002686
Neymeyer V Tephly T R and Miller M W (1997) Folate and 10-
formyltetrahydrofolate dehydrogenase (FDH) expression in the
central nervous system of the mature rat Brain Res 766 195 ndash 204
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Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase
Biochem Biophys Res Commun 67 610 ndash 616
Nishimura M and Naito S (2006) Tissue-speci1047297c mRNA expression
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cytochrome P450 and phase II metabolizing enzymes Drug
Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
(SSAO) activity a review Life Sci 79 417 ndash 422
Obata T and Yamanaka Y (2000) Evidence for existence of
immobilization stress-inducible semicarbazide-sensitive amine
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Oldham M C Konopka G Iwamoto K Langfelder P Kato T
Horvath S and Geschwind D (2008) Functional organization of
the transcriptome in the human brain Nat Neurosci 11 1271 ndash
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Tipton K F (2004) Semicarbazide-sensitive amine oxidases
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Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D
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Prasannan P Pike S Peng K Shane B and Appling D R (2003)
Human mitochondrial C1-tetrahydrofolate synthase gene structure
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Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
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Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
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Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
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Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
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Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux
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Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c
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synovial sarcomas rhabdomyosarcomas desmoplastic small round
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Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
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Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
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Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
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Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
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Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
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Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
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Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
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Staub F Peters J Kempski O Schneider G H Schurer Land Baethmann A (1993) Swelling of glial cells in lactacidosis
and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash
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Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
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Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
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the ventral but not dorsal hippocampus impairment of
parvalbumin neurons gamma oscillations and related behaviors
J Neurosci 30 2547 ndash 2558
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Formaldehyde in brain 19
7212019 Journal of Neurochemistry
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Stewart M J Malek K and Crabb D W (1996) Distribution of
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Sullivan P G and Brown M R (2005) Mitochondrial aging and
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Biol Psychiatry 29 407 ndash 410
Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
Magistretti P J and Alberini C M (2011) Astrocyte-neuron
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Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
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Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
neurotoxicity to PC12 cells involving inhibition of paraoxonase-1
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214
Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
1041
Thigpen A E West M G and Appling D R (1990) Rat C1-
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Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
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Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
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Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
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Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
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Tong Z Han C Luo W et al (2013b) Aging-associated excess
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Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
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Tulpule K and Dringen R (2012) Formate generated by cellular
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cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
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Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
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Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
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Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
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Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
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Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
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Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
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GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
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Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
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Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
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Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
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(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1215
Kiernan J A (2000) Formaldehyde formalin paraformaldehyde and
glutaraldehyde what they are and what they do Microsc Today 1
8 ndash 12
Kiernan M C Vucic S Cheah B C Turner M R Eisen A Hardiman
O Burrell J R and Zoing M C (2011) Amyotrophic lateral
sclerosis Lancet 377 942 ndash 955Kilburn K H Seidman B C and Warshaw R (1985a) Neurobehavioral
and respiratory symptoms of formaldehyde and xylene exposure in
histology technicians Arch Environ Health 40 229 ndash 233
Kilburn K H Warshaw R Boylen C T Johnson S J Seidman B
Sinclair R and Takaro T Jr (1985b) Pulmonary and
neurobehavioral effects of formaldehyde exposure Arch
Environ Health 40 254 ndash 260
Krupenko S A (2009) FDH an aldehyde dehydrogenase fusion enzyme
in folate metabolism Chem Biol Interact 178 84 ndash 93
Krupenko N I Dubard M E Strickland K C Moxley K M Oleinik
N V and Krupenko S A (2010) ALDH1L2 is the mitochondrial
homolog of 10-formyltetrahydrofolate dehydrogenase J Biol
Chem 285 23056 ndash 23063
Kurkijarvi R Yegutkin G G Gunson B K Jalkanen S Salmi M and
Adams D H (2000) Circulating soluble vascular adhesion protein1 accounts for the increased serum monoamine oxidase activity in
chronic liver disease Gastroenterology 119 1096 ndash 1103
Laitinen J Makela M Mikkola J and Huttu I (2010) Fire 1047297ghting
trainersrsquo exposure to carcinogenic agents in smoke diving
simulators Toxicol Lett 192 61 ndash 65
Lee E S Chen H Hardman C Simm A and Charlton C (2008)
Excessive S-adenosyl-L-methionine-dependent methylation
increases levels of methanol formaldehyde and formic acid in rat
brain striatal homogenates possible role in S-adenosyl-
L-methionine-induced Parkinsonrsquos disease-like disorders Life
Sci 83 821 ndash 827
Lee M Schwab C and McGeer P L (2011) Astrocytes are GABAergic
cells that modulate microglial activity Glia 59 152 ndash 165
Leuner K Muller W E and Reichert A S (2012) From mitochondrial
dysfunction to amyloid beta formation novel insights into thepathogenesis of Alzheimer rsquos disease Mol Neurobiol 46 186 ndash
193
Lewerenz J Dargusch R and Maher P (2010) Lactacidosis modulates
glutathione metabolism and oxidative glutamate toxicity
J Neurochem 113 502 ndash 514
Li F Liu X Su Z and Sun R (2011) Acidosis leads to brain
dysfunctions through impairing cortical GABAergic neurons
Biochem Biophys Res Commun 410 775 ndash 779
Li F Gong Q Dong H and Shi J (2012) Resveratrol a neuroprotective
supplement for Alzheimer rsquos disease Curr Pharm Des 18 27 ndash 33
Lim S Janzer A Becker A Zimmer A Schule R Buettner R and
Kirfel J (2010) Lysine-speci1047297c demethylase 1 (LSD1) is highly
expressed in ER-negative breast cancers and a biomarker
predicting aggressive biology Carcinogenesis 31 512 ndash 520
Lu S C (2013) Glutathione synthesis Biochim Biophys Acta 18303143 ndash 3153
Lu Z Li C M Qiao Y Yan Y and Yang X (2008) Effect of inhaled
formaldehyde on learning and memory of mice Indoor Air 18 77 ndash
83
Lu J Li C Su T Liu Y and He R (2013) Formaldehyde induces
hyperphosphorylation and polymerization of Tau protein both
in vitro and in vivo Biochim Biophys Acta 1830 4102 ndash 4116
Luo F C Zhou J Lv T Qi L Wang S D Nakamura H Yodoi J and
Bai J (2012) Induction of endoplasmic reticulum stress and the
modulation of thioredoxin-1 in formaldehyde-induced
neurotoxicity Neurotoxicology 33 290 ndash 298
Lushchak V I (2012) Glutathione homeostasis and functions potential
targets for medical interventions J Amino Acids 2012 736837
MacAllister S L Choi J Dedina L and OrsquoBrien P J (2011) Metabolic
mechanisms of methanolformaldehyde in isolated rat hepatocytes
Carbonyl-metabolizing enzymes versus oxidative stress Chem
Biol Interact 191 308 ndash 314
MacFarlane A J Perry C A Girnary H H Gao D Allen R H
Stabler S P Shane B and Stover P J (2009) Mthfd1 is anessential gene in mice and alters biomarkers of impaired one-
carbon metabolism J Biol Chem 284 1533 ndash 1539
Mahad D Ziabreva I Lassmann H and Turnbull D (2008)
Mitochondrial defects in acute multiple sclerosis lesions Brain
131 1722 ndash 1735
Malek F A Moritz K U and Fanghanel J (2003) A study on speci1047297c
behavioral effects of formaldehyde in the rat J Exp Anim Sci 42
160 ndash 170
del Mar Hernandez M Esteban M Szabo P Boada M and Unzeta M
(2005) Human plasma semicarbazide sensitive amine oxidase
(SSAO) b-amyloid protein and aging Neurosci Lett 384183 ndash 187
Martinez S E Vaglenova J Sabria J Martinez M C Farres J and
Pares X (2001) Distribution of alcohol dehydrogenase mRNA in
the rat central nervous system - consequences for brain ethanol and
retinoid metabolism Eur J Biochem 268 5045 ndash 5056Mason M J Mattsson K Pasternack M Voipio J and Kaila K (1990)
Postsynaptic fall in intracellular pH and increase in surface pH
caused by ef 1047298ux of formate and acetate anions through GABA-
gated channels in cray1047297sh muscle-1047297bers Neuroscience 34 359 ndash
368
Meinerz D F Comprasi B Allebrandt J et al (2013) Sub-acute
administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido)
succinate induces toxicity and oxidative stress in mice unexpected
effects of N-acetylcysteine Springerplus 2 182
Meszaros Z Szombathy T Raimondi L Karadi I Romics L and
Magyar K (1999) Elevated serum semicarbazide-sensitive amine
oxidase activity in non-insulin-dependent diabetes mellitus
correlation with body mass index and serum triglyceride
Metabolism 48 113 ndash 117
Metz B Kersten G F Hoogerhout P et al (2004) Identi1047297cation of formaldehyde-induced modi1047297cations in proteins reactions with
model peptides J Biol Chem 279 6235 ndash 6243
Metz B Kersten G F Baart G J de Jong A Meiring H ten Hove J
van Steenbergen M J Hennink W E Crommelin D J and
Jiskoot W (2006) Identi1047297cation of formaldehyde-induced
modi1047297cations in proteins reactions with insulin Bioconjug
Chem 17 815 ndash 822
Miao J and He R (2012) Chronic formaldehyde-mediated impairments
and age-related dementia in Neurodegeneration (Martin L M and
Loh S H Y eds) pp 59 ndash 76 InTech doi 10577234949
Monte W C (2010) Methanol a chemical Trojan horse as the root of the
inscrutable U Med Hypotheses 74 493 ndash 496
Moschen I Broer A Galic S Lang F and Broer S (2012) Signi1047297cance
of short chain fatty acid transport by members of the
monocarboxylate transporter family (MCT) Neurochem Res 372562 ndash 2568
Mukherjee S and Manahan-Vaughan D (2013) Role of metabotropic
glutamate receptors in persistent forms of hippocampal plasticity
and learning Neuropharmacology 66 65 ndash 81
Nazarian A Hermannsson B J Muller J Zurakowski D and Snyder
B D (2009) Effects of tissue preservation on murine bone
mechanical properties J Biomech 42 82 ndash 86
Neves A Costalat R and Pellerin L (2012) Determinants of brain
cell metabolic phenotypes and energy substrate utilization unraveled
with a modeling approach PLoS Comput Biol 8 e1002686
Neymeyer V Tephly T R and Miller M W (1997) Folate and 10-
formyltetrahydrofolate dehydrogenase (FDH) expression in the
central nervous system of the mature rat Brain Res 766 195 ndash 204
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
18 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1315
Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase
Biochem Biophys Res Commun 67 610 ndash 616
Nishimura M and Naito S (2006) Tissue-speci1047297c mRNA expression
pro1047297les of human phase I metabolizing enzymes except for
cytochrome P450 and phase II metabolizing enzymes Drug
Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
(SSAO) activity a review Life Sci 79 417 ndash 422
Obata T and Yamanaka Y (2000) Evidence for existence of
immobilization stress-inducible semicarbazide-sensitive amine
oxidase inhibitor in rat brain cytosol Neurosci Lett 296 58 ndash 60
Oldham M C Konopka G Iwamoto K Langfelder P Kato T
Horvath S and Geschwind D (2008) Functional organization of
the transcriptome in the human brain Nat Neurosci 11 1271 ndash
1282
Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide
diversity of function and pharmacology Neuropharmacology 56
141 ndash 148
OrsquoSullivan J Unzeta M Healy J OrsquoSullivan M I Davey G and
Tipton K F (2004) Semicarbazide-sensitive amine oxidases
enzymes with quite a lot to do Neurotoxicology 25 303 ndash 315Oyama Y Sakai H Arata T Okano Y Akaike N Sakai K and Noda
K (2002) Cytotoxic effects of methanol formaldehyde and
formate on dissociated rat thymocytes a possibility of aspartame
toxicity Cell Biol Toxicol 18 43 ndash 50
Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D
(2011) Energy failure in multiple sclerosis and its investigation
using MR techniques J Neurol 258 2113 ndash 2127
Parnetti L Reboldi G P and Gallai V (2000) Cerebrospinal 1047298uid
pyruvate levels in Alzheimer rsquos disease and vascular dementia
Neurology 54 735 ndash 737
Pauwels P J Opperdoes F R and Trouet A (1985) Effects of
antimycin glucose deprivation and serum on cultures of neurons
astrocytes and neuroblastoma cells J Neurochem 44 143 ndash 148
Pitten F A Kramer A Herrmann K Breme I and Koch S (2000)
Formaldehyde neurotoxicity in animal experiments Pathol ResPract 196 193 ndash 198
Prasannan P Pike S Peng K Shane B and Appling D R (2003)
Human mitochondrial C1-tetrahydrofolate synthase gene structure
tissue distribution of the mRNA and immunolocalization in
Chinese hamster ovary cells J Biol Chem 278 43178 ndash 43187
Regan R F and Guo Y P (1999a) Extracellular reduced glutathione
increases neuronal vulnerability to combined chemical hypoxia and
glucose deprivation Brain Res 817 145 ndash 150
Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
high concentrations of extracellular reduced glutathione
Neuroscience 91 463 ndash 470
Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
Merillon J M and Monti J P (2011) Neuroprotective properties
of resveratrol and derivatives Ann N Y Acad Sci 1215 103 ndash
108Rose C F (2010) Increase brain lactate in hepatic encephalopathy cause
or consequence Neurochem Int 57 389 ndash 394
Ross J M Oberg J Brene S et al (2010) High brain lactate is a
hallmark of aging and caused by a shift in the lactate
dehydrogenase AB ratio Proc Natl Acad Sci USA 107
20087 ndash 20092
Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
indoor environment Chem Rev 110 2536 ndash 2572
Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
Ozen Q A Turgut M and Bas O (2007) Effects of postnatal
formaldehyde exposure on pyramidal cell number volume of cell
layer in hippocampus and hemisphere in the rat a stereological
study Brain Res 1145 157 ndash 167
Sasseville D (2004) Hypersensitivity to preservatives Dermatol Ther
17 251 ndash 263
Schad A Fahimi H D Volkl A and Baumgart E (2003) Expression
of catalase mRNA and protein in adult rat brain detectionby nonradioactive in situ hybridization with signal ampli1047297cation
by catalyzed reporter deposition (ISH-CAR D) and
immunohistochemistry (IHC)immuno1047298uorescence (IF) J
Histochem Cytochem 51 751 ndash 760
Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux
in cultured astrocytes Neurochem Res 36 894 ndash 903
Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c
demethylase 1 is highly expressed in solitary 1047297brous tumors
synovial sarcomas rhabdomyosarcomas desmoplastic small round
cell tumors and malignant peripheral nerve sheath tumors Hum
Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
1029 ndash 1050 Neural Metabolism in vivo Springer New York
Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
neuroblastoma implications for therapy Cancer Res 69 2065 ndash
2071
Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
by 2-step demyelination Med Hypotheses 12 129 ndash 142
Skrzydlewska E (2003) Toxicological and metabolic consequences of
methanol poisoning Toxicol Mech Methods 13 277 ndash 293
Smith D J and Vainio P J (2007) Targeting vascular adhesion protein-
1 to treat autoimmune and in1047298ammatory diseases Ann N Y Acad
Sci 1110 382 ndash 388
Sohal R S and Orr W C (2012) The redox stress hypothesis of aging
Free Radic Biol Med 52 539 ndash 555
Song M S Baker G B Dursun S M and Todd K G (2010) The
antidepressant phenelzine protects neurons and astrocytes
against formaldehyde-induced toxicity J Neurochem 1141405 ndash 1413
Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
Ilhan N (2008) The effects of inhaled formaldehyde on oxidant and
antioxidant systems of rat cerebellum during the postnatal
development process Toxicol Mech Methods 18 569 ndash 574
Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
formaldehyde on the nervous system Rev Environ Contam
Toxicol 203 105 ndash 118
Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
formaldehyde exposure produces enhanced fear conditioning to
odor in male but not female rats Brain Res 1008 11 ndash 19
Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
(2009) The janus face of alcohol dehydrogenase 3 Chem Biol
Interact 178 29 ndash 35
Staub F Peters J Kempski O Schneider G H Schurer Land Baethmann A (1993) Swelling of glial cells in lactacidosis
and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash
74
Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
less support implications for Alzheimer rsquos disease Neurobiol
Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
P Cuenod M and Do K Q (2010) Redox dysregulation affects
the ventral but not dorsal hippocampus impairment of
parvalbumin neurons gamma oscillations and related behaviors
J Neurosci 30 2547 ndash 2558
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 19
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1415
Stewart M J Malek K and Crabb D W (1996) Distribution of
messenger RNAs for aldehyde dehydrogenase 1 aldehyde
dehydrogenase 2 and aldehyde dehydrogenase 5 in human
tissues J Investig Med 44 42 ndash 46
Sullivan P G and Brown M R (2005) Mitochondrial aging and
dysfunction in Alzheimer rsquos disease Prog Neuropsychopharmacol
Biol Psychiatry 29 407 ndash 410
Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
Magistretti P J and Alberini C M (2011) Astrocyte-neuron
lactate transport is required for long-term memory formation Cell
144 810 ndash 823
Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
and health effects Environ Int 35 1210 ndash 1224
Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
neurotoxicity to PC12 cells involving inhibition of paraoxonase-1
expression and activity Clin Exp Pharmacol Physiol 38 208 ndash
214
Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
1041
Thigpen A E West M G and Appling D R (1990) Rat C1-
tetrahydrofolate synthase cDNA isolation tissue-speci1047297c levels of
the mRNA and expression of the protein in yeast J Biol Chem
265 7907 ndash 7913
Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
dehydrogenase beyond phase I metabolism Toxicol Lett 193
1 ndash 3
Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev
Nutr 30 57 ndash 81
Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
formaldehyde and acidic microenvironment synergistically induce
bone cancer pain PLoS ONE 5 e10234
Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
inversely correlated to mini mental state examination scores in
senile dementia Neurobiol Aging 32 31 ndash 41
Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
R (2013a) Accumulated hippocampal formaldehyde induces age-
dependent memory decline Age (Dordr) 35 583 ndash 596
Tong Z Han C Luo W et al (2013b) Aging-associated excess
formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635
Tulpule K and Dringen R (2012) Formate generated by cellular
oxidation of formaldehyde accelerates the glycolytic 1047298ux in
cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
Neurochem Int 61 1302 ndash 1313
Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
metabolism and formaldehyde-induced stimulation of lactate
production and glutathione export in cultured neurons
J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
performance study Erciyes Med J 30 211 ndash 217
Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74
Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
vasculature pathological synergy of Alzheimer rsquos disease and
diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
(1997) Mitochondria-mediated cell injury Symposium overview
Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1315
Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase
Biochem Biophys Res Commun 67 610 ndash 616
Nishimura M and Naito S (2006) Tissue-speci1047297c mRNA expression
pro1047297les of human phase I metabolizing enzymes except for
cytochrome P450 and phase II metabolizing enzymes Drug
Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase
(SSAO) activity a review Life Sci 79 417 ndash 422
Obata T and Yamanaka Y (2000) Evidence for existence of
immobilization stress-inducible semicarbazide-sensitive amine
oxidase inhibitor in rat brain cytosol Neurosci Lett 296 58 ndash 60
Oldham M C Konopka G Iwamoto K Langfelder P Kato T
Horvath S and Geschwind D (2008) Functional organization of
the transcriptome in the human brain Nat Neurosci 11 1271 ndash
1282
Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide
diversity of function and pharmacology Neuropharmacology 56
141 ndash 148
OrsquoSullivan J Unzeta M Healy J OrsquoSullivan M I Davey G and
Tipton K F (2004) Semicarbazide-sensitive amine oxidases
enzymes with quite a lot to do Neurotoxicology 25 303 ndash 315Oyama Y Sakai H Arata T Okano Y Akaike N Sakai K and Noda
K (2002) Cytotoxic effects of methanol formaldehyde and
formate on dissociated rat thymocytes a possibility of aspartame
toxicity Cell Biol Toxicol 18 43 ndash 50
Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D
(2011) Energy failure in multiple sclerosis and its investigation
using MR techniques J Neurol 258 2113 ndash 2127
Parnetti L Reboldi G P and Gallai V (2000) Cerebrospinal 1047298uid
pyruvate levels in Alzheimer rsquos disease and vascular dementia
Neurology 54 735 ndash 737
Pauwels P J Opperdoes F R and Trouet A (1985) Effects of
antimycin glucose deprivation and serum on cultures of neurons
astrocytes and neuroblastoma cells J Neurochem 44 143 ndash 148
Pitten F A Kramer A Herrmann K Breme I and Koch S (2000)
Formaldehyde neurotoxicity in animal experiments Pathol ResPract 196 193 ndash 198
Prasannan P Pike S Peng K Shane B and Appling D R (2003)
Human mitochondrial C1-tetrahydrofolate synthase gene structure
tissue distribution of the mRNA and immunolocalization in
Chinese hamster ovary cells J Biol Chem 278 43178 ndash 43187
Regan R F and Guo Y P (1999a) Extracellular reduced glutathione
increases neuronal vulnerability to combined chemical hypoxia and
glucose deprivation Brain Res 817 145 ndash 150
Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by
high concentrations of extracellular reduced glutathione
Neuroscience 91 463 ndash 470
Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P
Merillon J M and Monti J P (2011) Neuroprotective properties
of resveratrol and derivatives Ann N Y Acad Sci 1215 103 ndash
108Rose C F (2010) Increase brain lactate in hepatic encephalopathy cause
or consequence Neurochem Int 57 389 ndash 394
Ross J M Oberg J Brene S et al (2010) High brain lactate is a
hallmark of aging and caused by a shift in the lactate
dehydrogenase AB ratio Proc Natl Acad Sci USA 107
20087 ndash 20092
Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the
indoor environment Chem Rev 110 2536 ndash 2572
Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T
Ozen Q A Turgut M and Bas O (2007) Effects of postnatal
formaldehyde exposure on pyramidal cell number volume of cell
layer in hippocampus and hemisphere in the rat a stereological
study Brain Res 1145 157 ndash 167
Sasseville D (2004) Hypersensitivity to preservatives Dermatol Ther
17 251 ndash 263
Schad A Fahimi H D Volkl A and Baumgart E (2003) Expression
of catalase mRNA and protein in adult rat brain detectionby nonradioactive in situ hybridization with signal ampli1047297cation
by catalyzed reporter deposition (ISH-CAR D) and
immunohistochemistry (IHC)immuno1047298uorescence (IF) J
Histochem Cytochem 51 751 ndash 760
Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux
in cultured astrocytes Neurochem Res 36 894 ndash 903
Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c
demethylase 1 is highly expressed in solitary 1047297brous tumors
synovial sarcomas rhabdomyosarcomas desmoplastic small round
cell tumors and malignant peripheral nerve sheath tumors Hum
Pathol 42 1667 ndash 1675
Schmidt M M and Dringen R (2012) GSH synthesis and metabolism
in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp
1029 ndash 1050 Neural Metabolism in vivo Springer New York
Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated
neuroblastoma implications for therapy Cancer Res 69 2065 ndash
2071
Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused
by 2-step demyelination Med Hypotheses 12 129 ndash 142
Skrzydlewska E (2003) Toxicological and metabolic consequences of
methanol poisoning Toxicol Mech Methods 13 277 ndash 293
Smith D J and Vainio P J (2007) Targeting vascular adhesion protein-
1 to treat autoimmune and in1047298ammatory diseases Ann N Y Acad
Sci 1110 382 ndash 388
Sohal R S and Orr W C (2012) The redox stress hypothesis of aging
Free Radic Biol Med 52 539 ndash 555
Song M S Baker G B Dursun S M and Todd K G (2010) The
antidepressant phenelzine protects neurons and astrocytes
against formaldehyde-induced toxicity J Neurochem 1141405 ndash 1413
Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and
Ilhan N (2008) The effects of inhaled formaldehyde on oxidant and
antioxidant systems of rat cerebellum during the postnatal
development process Toxicol Mech Methods 18 569 ndash 574
Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of
formaldehyde on the nervous system Rev Environ Contam
Toxicol 203 105 ndash 118
Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level
formaldehyde exposure produces enhanced fear conditioning to
odor in male but not female rats Brain Res 1008 11 ndash 19
Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O
(2009) The janus face of alcohol dehydrogenase 3 Chem Biol
Interact 178 29 ndash 35
Staub F Peters J Kempski O Schneider G H Schurer Land Baethmann A (1993) Swelling of glial cells in lactacidosis
and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash
74
Steele M L and Robinson S R (2012) Reactive astrocytes give neurons
less support implications for Alzheimer rsquos disease Neurobiol
Aging 33 423e1 ndash 423e13
Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T
P Cuenod M and Do K Q (2010) Redox dysregulation affects
the ventral but not dorsal hippocampus impairment of
parvalbumin neurons gamma oscillations and related behaviors
J Neurosci 30 2547 ndash 2558
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 19
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1415
Stewart M J Malek K and Crabb D W (1996) Distribution of
messenger RNAs for aldehyde dehydrogenase 1 aldehyde
dehydrogenase 2 and aldehyde dehydrogenase 5 in human
tissues J Investig Med 44 42 ndash 46
Sullivan P G and Brown M R (2005) Mitochondrial aging and
dysfunction in Alzheimer rsquos disease Prog Neuropsychopharmacol
Biol Psychiatry 29 407 ndash 410
Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
Magistretti P J and Alberini C M (2011) Astrocyte-neuron
lactate transport is required for long-term memory formation Cell
144 810 ndash 823
Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
and health effects Environ Int 35 1210 ndash 1224
Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
neurotoxicity to PC12 cells involving inhibition of paraoxonase-1
expression and activity Clin Exp Pharmacol Physiol 38 208 ndash
214
Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
1041
Thigpen A E West M G and Appling D R (1990) Rat C1-
tetrahydrofolate synthase cDNA isolation tissue-speci1047297c levels of
the mRNA and expression of the protein in yeast J Biol Chem
265 7907 ndash 7913
Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
dehydrogenase beyond phase I metabolism Toxicol Lett 193
1 ndash 3
Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev
Nutr 30 57 ndash 81
Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
formaldehyde and acidic microenvironment synergistically induce
bone cancer pain PLoS ONE 5 e10234
Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
inversely correlated to mini mental state examination scores in
senile dementia Neurobiol Aging 32 31 ndash 41
Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
R (2013a) Accumulated hippocampal formaldehyde induces age-
dependent memory decline Age (Dordr) 35 583 ndash 596
Tong Z Han C Luo W et al (2013b) Aging-associated excess
formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635
Tulpule K and Dringen R (2012) Formate generated by cellular
oxidation of formaldehyde accelerates the glycolytic 1047298ux in
cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
Neurochem Int 61 1302 ndash 1313
Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
metabolism and formaldehyde-induced stimulation of lactate
production and glutathione export in cultured neurons
J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
performance study Erciyes Med J 30 211 ndash 217
Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74
Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
vasculature pathological synergy of Alzheimer rsquos disease and
diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
(1997) Mitochondria-mediated cell injury Symposium overview
Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1415
Stewart M J Malek K and Crabb D W (1996) Distribution of
messenger RNAs for aldehyde dehydrogenase 1 aldehyde
dehydrogenase 2 and aldehyde dehydrogenase 5 in human
tissues J Investig Med 44 42 ndash 46
Sullivan P G and Brown M R (2005) Mitochondrial aging and
dysfunction in Alzheimer rsquos disease Prog Neuropsychopharmacol
Biol Psychiatry 29 407 ndash 410
Suzuki A Stern S A Bozdagi O Huntley G W Walker R H
Magistretti P J and Alberini C M (2011) Astrocyte-neuron
lactate transport is required for long-term memory formation Cell
144 810 ndash 823
Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)
Formaldehyde in China production consumption exposure levels
and health effects Environ Int 35 1210 ndash 1224
Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces
neurotoxicity to PC12 cells involving inhibition of paraoxonase-1
expression and activity Clin Exp Pharmacol Physiol 38 208 ndash
214
Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de
prevents formaldehyde-induced neurotoxicity to PC12 cells by
attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24
Teng S Beard K Pourahmad J Moridani M Easson E Poon R and
OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation
enzyme systems and molecular cytotoxic mechanism in isolated rat
hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296
Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash
1041
Thigpen A E West M G and Appling D R (1990) Rat C1-
tetrahydrofolate synthase cDNA isolation tissue-speci1047297c levels of
the mRNA and expression of the protein in yeast J Biol Chem
265 7907 ndash 7913
Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde
dehydrogenase beyond phase I metabolism Toxicol Lett 193
1 ndash 3
Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev
Nutr 30 57 ndash 81
Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived
formaldehyde and acidic microenvironment synergistically induce
bone cancer pain PLoS ONE 5 e10234
Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is
inversely correlated to mini mental state examination scores in
senile dementia Neurobiol Aging 32 31 ndash 41
Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He
R (2013a) Accumulated hippocampal formaldehyde induces age-
dependent memory decline Age (Dordr) 35 583 ndash 596
Tong Z Han C Luo W et al (2013b) Aging-associated excess
formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807
Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-
mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635
Tulpule K and Dringen R (2012) Formate generated by cellular
oxidation of formaldehyde accelerates the glycolytic 1047298ux in
cultured astrocytes Glia 60 582 ndash 593
Tulpule K Schmidt M M Boecker K Goldbaum O Richter-
Landsberg C and Dringen R (2012) Formaldehyde induces rapid
glutathione export from viable oligodendroglial OLN-93 cells
Neurochem Int 61 1302 ndash 1313
Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde
metabolism and formaldehyde-induced stimulation of lactate
production and glutathione export in cultured neurons
J Neurochem 125 260 ndash 272
Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)
Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-
induced learning and memory disabilities a labyrinth test
performance study Erciyes Med J 30 211 ndash 217
Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol
with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74
Unzeta M Sole M B oada M and Hernandez M (2007)
Semicarbazide-sensitive amine oxidase (SSAO) and its possible
contribution to vascular damage in Alzheimer rsquos disease J Neural
Transm 114 857 ndash 862
Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash
430
Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of
acute and subacute formaldehyde exposures in mice Environ
Toxicol Pharmacol 11 93 ndash 100
Valente T Gella A Sole M Durany N and Unzeta M (2012)
Immunohistochemical study of semicarbazide-sensitive amine
oxidasevascular adhesion protein-1 in the hippocampal
vasculature pathological synergy of Alzheimer rsquos disease and
diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of
GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250
Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P
(1997) Mitochondria-mediated cell injury Symposium overview
Fundam Appl Toxicol 38 23 ndash 37
Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of
aldehyde dehydrogenase-2 genetic polymorphisms on metabolism
of structurally different aldehydes in human liver Drug Metab
Dispos 30 69 ndash 73
Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M
Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)
Design synthesis and biological evaluation of semicarbazide-
sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory
activity J Med Chem 49 2166 ndash 2173
Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study
of chemical exposures and amyotrophic lateral sclerosis J Neurol
Neurosurg Psychiatry 80 558 ndash 561
Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the
putative demethylase gene s-JMJD1C is a coactivator of the AR
Arch Biochem Biophys 460 56 ndash 66
Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine
4 demethylase up-regulated in prostate cancer Proc Natl Acad
Sci USA 104 19226 ndash 19231
Yin J and Zhang J (2011) Multidrug resistance-associated protein 1
( MRP1ABCC1) polymorphism from discovery to clinical
application J Cent South Univ 36 927 ndash 938
Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive
amine oxidase in the pathogenesis of Alzheimer rsquos disease and
vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D
(2003) Physiological and pathological implications of
semicarbazide-sensitive amine oxidase Biochim Biophys Acta
1647 193 ndash 199
Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M
(2006) Protective effects of x-3 essential fatty acids against
formaldehyde-induced neuronal damage in prefrontal cortex of
rats Cell Biochem Funct 24 237 ndash 244
Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and
Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced
neurotoxicity in prefrontal cortex of rats An immunohistochemical
and biochemical study Cell Biochem Funct 25 413 ndash 418
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
20 K Tulpule and R Dringen
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21
7212019 Journal of Neurochemistry
httpslidepdfcomreaderfulljournal-of-neurochemistry 1515
Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut
S (2011) Protective effects of omega-3 essential fatty acids against
formaldehyde-induced cerebellar damage in rats Toxicol Ind
Health 27 489 ndash 495
Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su
Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia
Neurosci Res 68 66 ndash 72
Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads
to neurological disorders through overexciting cortical
pyramidal neurons Biochem Biophys Res Commun 415 224 ndash
228
Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C
Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative
splicing of the histone demethylase LSD1KDM1 contributes to the
modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532
Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat
brain aminergic neurons as possible targets for ethanol effects
Alcohol Alcohol 31 167 ndash 174
copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21
Formaldehyde in brain 21