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Review ArticleMitochondria-Targeted Protective Compounds
inParkinsons and Alzheimers Diseases
Carlos Fernndez-Moriano, Elena Gonzlez-Burgos, and M. Pilar
Gmez-Serranillos
Department of Pharmacology, Faculty of Pharmacy, University
Complutense of Madrid, 28040 Madrid, Spain
Correspondence should be addressed to M. Pilar
Gomez-Serranillos; [email protected]
Received 30 December 2014; Revised 25 March 2015; Accepted 27
March 2015
Academic Editor: Giuseppe Cirillo
Copyright 2015 Carlos Fernandez-Moriano et al. This is an open
access article distributed under the Creative CommonsAttribution
License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work isproperly
cited.
Mitochondria are cytoplasmic organelles that regulate both
metabolic and apoptotic signaling pathways; their most
highlightedfunctions include cellular energy generation in the form
of adenosine triphosphate (ATP), regulation of cellular
calciumhomeostasis, balance between ROS production and
detoxification, mediation of apoptosis cell death, and synthesis
andmetabolismof various keymolecules. Consistent evidence suggests
that mitochondrial failure is associated with early events in the
pathogenesisof ageing-related neurodegenerative disorders including
Parkinsons disease and Alzheimers disease.
Mitochondria-targetedprotective compounds that prevent or minimize
mitochondrial dysfunction constitute potential therapeutic
strategies in theprevention and treatment of these central nervous
system diseases. This paper provides an overview of the involvement
ofmitochondrial dysfunction in Parkinsons and Alzheimers diseases,
with particular attention to in vitro and in vivo studies
onpromising endogenous and exogenous mitochondria-targeted
protective compounds.
1. Introduction
Mitochondria are spherical cytoplasmic organelles with
asymbiotic origin that are present in all eukaryotic
cells.Structurally, mitochondria consist of two compositions
andfunctionally different phospholipid membranes referred toas the
outer membrane and the inner membrane and twoaqueous compartments,
the intermembrane space and themitochondrial matrix. The outer
membrane encloses theentire structure; it has higher content in
lipids (over 60%)and it contains porins and a large multiprotein
translocasecomplex allowing the passage to ions and larger
molecules.The inner membrane surrounds the mitochondrial matrixand
it invaginates to form cristae that increase total surfacearea. In
addition, the inner membrane has lipid content over20% and it is
only permeable to small uncharged molecules.Both membranes are
separated by the aqueous compartmentintermembrane space, located
between them [1, 2].Moreover,mitochondria contain their own DNA
(mDNA) held inthe mitochondrial matrix; the human mDNA is a
double-stranded circular genome made up of 16,569 base pairs of
DNA that encodes 13 proteins, 22 transfer RNAs (tRNAs), and2
ribosomal RNAs (rRNAs) [3]. Functionally, mitochondriaplay a vital
role in regulating both metabolic and apoptoticsignaling
pathways.Their main function is to produce energyas adenosine
triphosphate (ATP) at the mitochondrial elec-tron transport chain
(ETC) in the inner membrane, throughthe cellular process of
oxidative phosphorylation (OXPHOS).The mitochondrial ETC consists
of four integral membraneoxidation-reduction electron and proton
pump protein com-plexes (complex I, NADH:ubiquinone oxidoreductase;
com-plex II, succinate dehydrogenase; complex III,
ubiquinone-cytochrome oxidoreductase; complex IV, cytochrome
oxidase) and an ATP synthase (complex V) which catalyzesADP
conversion to form ATP [4]. In addition, mitochondriaparticipate in
other series of functions, including regulationof cellular calcium
homeostasis, balance between ROS pro-duction and detoxification
(i.e., superoxide anion (O
2
) andthe highly reactive hydroxyl radical (OH)), mediation of
theprocess of programmed cell death (apoptosis), and synthesisand
metabolism of endogenous compounds such as steroids,heme groups,
and fatty acids [5].
Hindawi Publishing CorporationOxidative Medicine and Cellular
LongevityVolume 2015, Article ID 408927, 30
pageshttp://dx.doi.org/10.1155/2015/408927
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2 Oxidative Medicine and Cellular Longevity
Consistent evidence suggests that mitochondrial failureis
associated with early events in the pathogenesis of ageing-related
neurodegenerative disorders including Parkinsonsdisease and
Alzheimers disease. Mitochondria-targeted pro-tective compounds
that prevent or minimize mitochondrialdysfunction constitute
potential therapeutic strategies in theprevention and treatment of
these central nervous systemdiseases [6, 7]. This paper provides an
overview of theinvolvement ofmitochondrial dysfunction in
Parkinsons andAlzheimers diseases, with particular attention to in
vitro andin vivo studies on promising endogenous and
exogenousmitochondria-targeted protective compounds.
2. Parkinsons Disease and Mitochondria-Targeted Protective
Compounds
2.1. Parkinsons Disease (PD). Parkinsons disease is a
chronicprogressive disorder characterized pathologically by the
lossof dopaminergic neurons located in the substantia nigrapars
compacta, and, to a lesser extent, in putamen, caudate,and globus
pallidus and by the formation of intracellularprotein inclusions of
mainly alpha-synuclein (named asLewy bodies) in the remaining
neurons [8, 9]. The firstclinical description was published in 1817
by the EnglishphysicianDr. Parkinson in his work An Essay on the
ShakingPalsy [10]. Parkinsons disease is the second most
commonneurodegenerative disorder after Alzheimers disease
whichaffects more than 6.3 million people over usually the ageof 60
worldwide. Regarding epidemiology, this age-relatedcentral nervous
system disease appears to be slightly morecommon in whites than
blacks and Asian people, in menthan inwomen, and in some
geographical regions (i.e., China,India, and USA) [1113]. The most
relevant clinical featuresinclude tremor, bradykinesia, rigidity,
and dystonia; however,in addition to these characteristicmotor
signs and symptoms,neuropsychiatric and other nonmotor
manifestations suchas depression, cognitive impairment, anxiety,
and psychosishave been also described [8, 9, 14]. Although the
exactcausal factors of Parkinsons disease remain unknown,
severalresearch studies point to specific genetic mutations
andenvironmental factors [15, 16]. It has been estimated thataround
510 in every 100 people suffering from Parkinsonsdisease are
associated with gene mutations. Scientifics haveidentified at least
13 gene mutations, among which one couldhighlight those in the
genes SNCA (synuclein, alpha non-A4 component of amyloid
precursor), PARK2 (Parkinsonsdisease autosomal recessive, juvenile
2), PARK7 (Parkinsonsdisease autosomal recessive, early-onset 7),
PINK1 (PTEN-induced putative kinase 1), and LRRK2 (leucine-rich
repeatkinase 2) [15].The SNCA gene encodes for the protein
alpha-synuclein, which is a key component of Lewy bodies; thePARK2
gene encodes for the E3 ubiquitin ligase parkin,which is implied in
mitochondrial maintenance; the PARK7gene encodes for the
antioxidant protein DJ-1; PINK 1gene encodes for a
serine/threonine-protein kinase with aprotective mitochondrial
role. Alterations of SNCA, PARK2,PARK7, and PINK1 genes are
involved in the early-onsetParkinsons disease (this is diagnosed
before being 50 years
old) [1720].The LRRK2 gene, which encodes for the
proteindardarin, has been associated with the late-onset
Parkinsonsdisease [21]. The rest, around 95%, of diagnosed
Parkinsonsdisease cases are sporadic, in which environmental
factorssuch as pesticides and dietary factors, among others, seemto
play a crucial role. Researchers have identified severalcommon
pesticides that their exposure may increase the riskof developing
Parkinsons disease among which rotenone,paraquat, dithiocarbamates
(i.e., maneb, ziram), pyrethroids(i.e., deltamethrin),
organochlorine (dieldrin), imidazoles(i.e., triflumizole, benomyl),
and 2,2-dicarboximides (i.e.,folpet, aptan) are included [22, 23].
Regarding dietary factors,both dietary patterns or/and dietary
nutrients that may pro-tect or may increase against to suffer from
Parkinsons diseasehave been reported. As an example, in a case
control studyperformed during ten years for establishing the
influence ofminerals, vitamins, and fats in the etiology of
Parkinsons dis-ease, an association between a high intake of a
combinationof iron and manganese and the development of
Parkinsonsdiseasewas found [24]. On the other hand, a large
prospectivestudy performed over fifteen years with 49 692 men and81
676 women revealed that the high intake of fruit, vegeta-bles,
legumes, whole grains, nuts, fish, and poultry, the lowintake of
saturated fat, and the moderate intake of alcohol areprotective
dietary patterns against Parkinsons disease [25].
2.1.1. Mitochondrial Dysfunction in Familial PD. As we
havepreviously commented, around 510% of Parkinsons dis-ease cases
involve gene products. Mutations in ATP13A2(PARK9), DJ-1 (PARK7),
parkin (PARK2), and PTEN-induced putative kinase 1 (PINK1) (PARK6)
are associatedwith autosomal recessive PD and mutations in
-synucleingene and leucine-rich repeat kinase 2 gene (LRRK2)
areimplicated in autosomal dominant PD (see Figure 1) [16].
Mutations in the ATP13A2 gene (PARK9), encodingfor a lysosomal
type 5P-type ATPase, cause a hereditaryrare juvenile onset
autosomal recessive Parkinsonism withdementia named as Kufor-Rakeb
syndrome. This particularParkinsons form, characterized by
supranuclear gaze palsy,dystonia, pyramidal signs, and cognitive
impairment, wasfirst evidenced in 2006 in members of a
nonconsanguineousChilean family. The neuronal damage associated
with muta-tions in this gene is related to alterations
inmitochondria andlysosomes functions and divalent cation
regulation [2628].
DJ-1 mutations on chromosome 1p36 cause autosomalrecessive
early-onset PD and its pathological mechanismseems to be linked
with mitochondrial fragmentation andmitochondrial structural damage
and consequently defects inthe mitochondrial function of
dopaminergic cells [29, 30].
Mutations in the parkin gene product, which is an ubiqui-tin
ligase, lead to an early-onset familial Parkinsons diseaseand its
first description dates in the year 1998. Experimentalstudies have
determined that the pathology of parkin isassociated with
alterations in the mitochondrial recogni-tion, transportation, and
ubiquitination and with mitophagyimpairment [31, 32].
Mutations in themitochondrial serine/threonine-proteinkinase
PINK1 result in alterations in the mitochondrial
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Oxidative Medicine and Cellular Longevity 3
III
IIIIV
V
Alpha-synuclein
PINK1
ATP production
PINK1
ROS
PINK1
Parkin
Mitochondrialpotential
LRRK2
LRRK2
Mitochondrialdysfunction
DJ-1
DJ-1
DJ-1
Figure 1: The role of gene products in Parkinsons disease.
morphology and function (defects in complex I activity)and they
are strongly associated with a form of autosomalrecessive
early-onset Parkinsons disease [33, 34].
Mutations in the protein -synuclein, which is the maincomponent
of Lewy bodies (it represents 1% of total cytosolicprotein of brain
cells), have been reported to play a keyrole in the pathogenesis of
autosomal dominant early-onsetParkinsons disease. Particularly, two
mutations in the alpha-synuclein gene (A30P and A53T) have been
identified whichlead to the formation of pathogenic pore-like
annular andtubular protofibrils. These mutations inhibit the
activity ofcomplex I and induce mitochondrial fragmentation,
causingmitochondrial dysfunction [35, 36].
Mutations in the gene encoding leucine-rich repeatkinase 2
(LRRK2) are related to autosomal dominant Parkin-sons disease form.
The most common mutation is G2019Sthat accounts for 5-6% of
familial cases of Parkinsons disease.Experimental studies have
identified different pathogenicmechanisms for altered LRRK2 that
involve inflammationprocesses, oxidative stress, and mitochondrial
dysfunction,among others. Focusing on this last pathogenic
mechanism,mutations in LRRK2 cause mitochondrial fragmentation anda
downregulation in mitochondrial homeostasis (reductionin
mitochondrial membrane potential and ATP production)[37, 38].
2.1.2. Mitochondrial Dysfunction in Sporadic PD. Around95% of
diagnosed Parkinsons disease cases are sporadic.One of the proposed
mechanisms for the dopaminergicneurons degeneration in sporadic
Parkinsons disease cases isrelated to an excessive production of
reactive oxygen species(ROS) that leads to oxidative stress
situation. An excess of
ROS causes the oxidative modification of macromolecules(lipids,
proteins, and DNA) leading to cell damage andeven cell death. The
pathological effect of ROS is alsoinvolved in a reduction of ATP
(adenosine triphosphate)production, in an increase of iron levels,
and in an increaseof intracellular calcium levels and alterations
in mitochon-drial respiratory chain complexes function. In addition
tooxidative stress mechanism, protein misfolding, aggregation,and
deposition have been reported as other common patho-logical
mechanisms in Parkinsons disease. A dysfunction inthe
ubiquitin-proteasome-system (UPS) and the autophagy-lysosomal
pathway (ALP) as evidenced in a reduction ofproteasome and
autophagy activities and in postmortembrains of patients suffering
from this neurodegenerativedisease has been demonstrated
[3943].
2.1.3. PostmortemPDBrain Tissues, ExperimentalModels,
andCell-Based Models. Many evidences from postmortem PDbrain
tissues, experimental models, and cell-based modelshave
demonstrated the involvement of mitochondria dys-function in the
pathogenesis of both familial and sporadicParkinsons disease.
The first evidence of the relationship between mitochon-dria and
Parkinsons disease dates from the second half ofthe twentieth
century when the postmortem brain analysisof some drug abusers of
intravenous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),
who have developed aprogressive and irreversible parkinsonism,
revealed a signifi-cant nigrostriatal degeneration. MPTP easily
passes throughthe blood-brain barrier; it is oxidized and
transformed into1-methyl-4-phenylpyridinium (MPP+) and within
neurons
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4 Oxidative Medicine and Cellular Longevity
MPP+ inhibits the complex I (NADH-quinone oxidore-ductase) of
the electron transport chain, resulting in anenhanced reactive
oxygen species (ROS) generation (i.e.,hydroxyl radicals, superoxide
anion radical) and a decrease inenergy supply (ATP production)
[44].Many lines of evidencehave further demonstrated complex I
deficiency or impair-ment in the cortical brain tissue, frontal
cortex, striatum,skeletal muscle, and platelets of patients with
Parkinsonsdisease [40, 45, 46]. In addition to complex I, other
studieshave reported that a deficiency in the activity of complexII
(succinate ubiquinone oxidoreductase) and complex
III(ubiquinol-cytochrome C oxidoreductase) is also associatedwith
the pathogenesis of Parkinsons disease. Complex IIIinhibition, as
what happens with complex I, causes an over-production of ROS,
leading to oxidation of lipids, proteins,and DNA and it finally
triggers to cell death [47, 48]. More-over, ROS mediates the
mitochondrial-dependent apoptosisby inducing mitochondrial
permeability transition, releasingof cytochrome c, activation of
caspase-3 and caspase-9,translocation of Bax to mitochondria, and
the activation ofc-Jun N-terminal kinase (JNK) and p38
mitogen-activatedprotein kinase (p38 MAPK) in the cytosol [49,
50].
The neurotransmitter dopamine has been also relatedto the
pathogenesis of Parkinsons disease. In vitro experi-mental
researches on neuronal cell types and isolated brainmitochondria
and in vivo studies using different animalmodels and postmortem
brain studies in Parkinsons diseasehave demonstrated that dopamine
oxidation and reactivedopamine quinone oxidation products
inducemitochondrialrespiration uncoupling and cause ATP levels
reduction andinactivate proteasomal activity, among other effects,
whichcontribute to mitochondrial dysfunction [5157]. The roleof
tetrahydrobiopterin (BH4) in Parkinsons disease etiologyis also
remarkable; BH4 is an obligatory cofactor for thedopamine synthesis
enzyme tyrosine hydroxylase and it ispresent selectively in
monoaminergic neurons in the brain.It has been suggested as an
endogenous molecule thatcontributes to the dopaminergic
neurodegeneration throughan inhibition of the activities of
complexes I and IV of theelectron transport chain (ETC), together
with a release ofmitochondrial cytochrome C and a reduction of
mitochon-drial membrane potential [58].
There are other studies which involve calcium excitotoxi-city
and nonexcitotoxicity relatedmechanisms in the etiologyof
Parkinsons disease. Alterations in calcium influx in neu-rons via
L-type voltage-dependent channels and N-methyl-D-aspartate (NMDA)
receptors may lead to an excitotoxiccellular calcium accumulation
that can cause mitochon-drial dysfunction by reducing ATP
production, activatingmitochondrial permeability transition,
increasing ROS gen-eration, and inducing mitochondrial-dependent
apoptosis[59, 60]. Other circumstances, not ordinarily toxic,
havebeen reported to contribute to mitochondrial dysfunction.Hence,
Sheehan et al. (1997) showed using mitochondriallytransformed cells
(cybrids) that the capacity to sequestratecalciumwas lower in
patients with Parkinsons disease than incontrol subjects,
suggesting that this homeostasis alterationcould increase neurons
cell death [61].
Regarding familial Parkinsons disease, mutations in sev-eral
genes previously reported (Parkin, PINK1, DJ-1, -synu-clein, and
LRRK2) which encode for mitochondrial proteinshave been identified
to contribute to mitochondrial dysfunc-tion [62, 63].
There are different neurotoxins including rotenone,
1-methyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydop-amine
(6-OHDA), and paraquat, among others, which havebeen extensively
used as Parkinsons disease experimentalmodels to mimic the
neuropathology of this neurodegener-ative disorder in both in vitro
(i.e., human neuroblastomaSK-N-SH cells) and in vivo (animals
models such as rats,mice) investigations and, consequently, to help
establishneuroprotective strategies. Rotenone, an insecticide
extractedfrom the roots of Derris spp. and Lonchocarpus spp.
(Legu-minosae family), acts by inhibiting the mitochondrial
res-piratory chain complex I [64]. Paraquat
(1,1-dimethyl-4,4-bipyridinium dichloride), which is a quaternary
nitrogenherbicide used to control weed growth, has been reported
toincrease ROS generation and induce-synuclein fibril forma-tion
[65]. The 1-methyl-1,2,3,6-tetrahydropyridine (MPTP),a byproduct
obtained during the chemical synthesis of ameperidine analog, is
metabolized in the brain to the toxiccompound MPP+ which inhibits
complex I of the electrontransport chain [44]. The
catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA), via
intracerebral infusion,causes the irreversible loss of
nigrostriatal dopaminergicneurons by inducing ROS production and
inhibiting complexI and complex IV of the electron transport chain
[66].
2.2. Mitochondria-Targeted Protective Compounds in PD.Endogenous
and exogenous compounds are in continuinginvestigation as
mitochondria-targeted agents to prevent ortreat Parkinsons disease
(Figure 2). Table 1 reports com-pounds that have been demonstrated
to be promising agentsin the protection of mitochondrial
dysfunction in differentParkinsons disease models. Hence, among the
endogenouscompounds investigated so far, the hormone melatonin,
theneuropeptide cocaine, and amphetamine regulated
transcript(CART), the ursodeoxycholic acid, the mitoQ
(mitoquinonemesylate), and the -lipoic acid can be highlighted.
Thehormone melatonin has been shown to exert in vivo mito-chondrial
protective action in MPTP-induced mice model,6-OHDA rat model, and
rotenone-induced rat model bymaintaining mitochondrial membrane
potential, increasingantioxidant enzymatic (i.e., SOD, CAT) and
nonenzymaticlevels (i.e., glutathione), inhibiting ROS
overproduction,increasing ATP production, decreasing calcium
concentra-tion levels, and enhancing mitochondrial complex I
activ-ity [6771]. The neuropeptide cocaine and amphetamineregulated
transcript (CART) protected mitochondrial DNAand cellular proteins
and lipids of human neuroblastomaSH-SY5Y cells, HEK293 cells, and
cultures of cortical andhippocampal neurons exposed to hydrogen
peroxide [72].The ursodeoxycholic acid (one of the secondary bile
acids)and the mitoQ (mitoquinone mesylate) acted as antiapop-totic
agent in human neuroblastoma SH-SY5Y cells treatedwith SNP and
6-OHDA, respectively [73, 74]. The -lipoic
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Oxidative Medicine and Cellular Longevity 5
III
IIIIV
V
Mitochondrial DNA
DNA damage
Apoptosis
Green tea polyphenols, melatonin
Mitochondrial
Mitochondrial
permeabilitytransition pore (MPTP)
membrane potentialMelatonin, lycopene
respiratory chain
Hesperidin, quercetin, -lipoic acid,xyloketal B, melatonin
Neuropeptide cocaine, amphetamineregulated transcript (CART)
Chunghyuldan, curcumin, hesperidin, green teapolyphenols,
pyruvate, quercetin, -lipoic acid,xyloketal B, melatonin,
rosmarinic acid, harmalol,harmine, lycopene, glutamoyl diester of
curcumin
Chunghyuldan, curcumin, pyruvate, silymarin,baicalein, tyrosol,
hesperidin, green tea polyphenols,quercetin, -lipoic acid,
xyloketal B, melatonin,rosmarinic acid, harmalol, harmine,
glutamoyldiester of curcumin
Ursodeoxycholic acid, licorice, Panax ginseng,MitoQ (mitoquinone
mesylate), caffeic acid phenethyl ester,salvianic acid A,
salvianolic acid B, protocatechuic acid,umbelliferone, esculetin,
osthole, Chunghyuldan, curcumin,silymarin, baicalein, tyrosol,
hesperidin, green tea polyphenols,pyruvate, isoborneol, piperine,
tetramethylpyrazine, astaxanthin
ROS
ROS Mitochondrial
ATP production
Ca2+
Mitochondrial Ca2+
Cytosolic Ca2+
Antioxidant system
Figure 2: Mechanisms of mitochondrial dysfunction and
mitochondria-targeted drugs that have produced beneficial effect in
PD models.
acid has been evaluated as mitochondrial-targeted protec-tive
compound in several in vitro and in vivo Parkinsonsdisease models
(i.e., PC12 cells, SK-N-MC cells, and ratmodel; toxins as MPP(+)
and rotenone); this organosulfurcompound derived fromoctanoic acid
protectsmitochondriaby inhibiting ROS production, increasing
glutathione levels,andmaintainingmitochondrialmembrane potential
[7578].Pyruvate has also been demonstrated in in vitro studies
thatmaintains mitochondrial membrane potential and inhibitsROS
generation and nuclear translocation of NF-kappaB aswell as
mitochondrial apoptotic pathway [79, 80].
Several natural products from medicinal plants, bothisolated
compounds and extracts, have been demonstrated inin vitro and in
vivo studies to exert promising mitochondrialprotection. As
extracts, it has been reported that berries richin anthocyanidins
and proanthocyanidins protect mitochon-dria from rotenone-induced
changes in the respiratory chain[118]. The silymarin, which is a
standardized extract of themilk thistle seeds, maintained
mitochondrial integrity andfunction and inhibited mitochondrial
apoptotic pathway inMPP(+)-induced ratmodel [119]. Green tea
polyphenols havebeen also evidenced to inhibit mitochondrial
apoptotic path-way (increasing Bcl2 and decreasing caspase-3
activity) andto maintain mitochondrial membrane potential, to
inhibitROS production and calcium concentration levels [120].
Thelicorice (root of Glycyrrhiza glabra) inhibited
dopaminergicapoptotic cell death as evidenced in the increase in
Bcl2levels and in the decrease in Bax levels, caspase-3
activity,cytochrome c release, and JNK andMAP activities in
amodelof 6-OHDA-induced Parkinsons disease [121]. The waterextract
of Panax ginseng also inhibited apoptosis MPP(+)-induced in the
human neuroblastoma SH-SY5Y cells bydecreasing Bax levels,
caspase-3 activity, and cytochromerelease and increasing Bcl2
levels [122].
The herbal medicine Chunghyuldan inhibited caspase-3,ROS
generation and maintained mitochondrial membranepotential in 6-OH
Parkinsons disease model [123]. Amongisolated natural products,
highlight those with polyphenolstructure.The polyphenol resveratrol
has been demonstratedin in vitro primary fibroblasts cultures from
patients withparkin mutations (PARK2) to regulate mitochondrial
energyhomeostasis as evidenced in the increment of complex
Iactivity, citrate synthase activity, basal oxygen consumption,and
ATP production and in the decrement of lactate content[111]. The
polyphenol hesperidin inhibited mitochondrialapoptotic pathway
(increased Bcl2 levels and decreased Bax,caspase-3, and caspase-9
activities and inhibited cytochromec release), maintained
mitochondrial membrane potential,inhibited ROS production, and
increased glutathione levelsin in vitro human neuroblastoma SK-N-SH
cells model ofrotenone-induced Parkinsons disease [98]. Quercetin
res-cued toxic-induced defects in mitochondria in in vitro andin
vivo experiments. Quercetin inhibited ROS generation andmaintained
mitochondria membrane potential in rotenone-induced rat model
[108]. Moreover, quercetin decreased theproduction of superoxide
radicals and inhibited the expres-sion of the inducible nitric
oxide synthase protein expressionin in vitro glial-neuronal system
model of MPP(+)-inducedParkinsons disease [109]. The flavonoid
baicalein inhibitedin vitro apoptotic mitochondrial cell death and
maintainedmitochondrial integrity and function in both SH-SYTY
andPC12 cells in 6-OHDA and rotenone Parkinsons diseasemodels as
evidenced in the decrease in caspase-3, caspase-7, caspase-9, and
JNK activities and in the maintenanceof mitochondrial membrane
potential, increment of ATPcontent and reduction of ROS production
[8284]. Thetyrosol protected CATH.a cells against MPP(+)-toxicity
byinhibiting apoptotic cell death via activation of PI3K/Akt
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6 Oxidative Medicine and Cellular Longevity
Table1:Parkinsons
diseasea
ndmito
chon
dria-ta
rgeted
protectiv
ecom
poun
ds.
Com
poun
dClasso
fcom
poun
dParkinsons
mod
elMechanism
sRe
ferences
Acetyl-L-carnitin
eQuaternary
ammon
ium
Invitro
human
neurob
lasto
maS
K-N-M
Ccells
mod
elof
roteno
ne-in
ducedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialbiogenesis
RO
Sgeneratio
n[65]
Astaxanthin
Non
provitamin
Acaroteno
id
MPP
(+)-indu
cedmou
semod
elIn
vitro
human
neurob
lasto
maS
K-N-SHcells
mod
elof
MPP
+-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xand-synuclein
caspase-3
[81]
Invitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
elof
6-OHDA-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
l;maintainmito
chon
drialredox
activ
ity[82]
Baicalein
Flavon
oid
Invitro
ratadrenalph
eochromocytom
aPC12cells
mod
eland
isolatedratb
rain
mito
chon
driaof
roteno
neindu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3andcaspase-7
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
nintracellularA
TPprod
uctio
n
[83]
Invitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
elof
6-OHDA-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lInhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3andcaspase-9
p-c-JunN-te
rminalkinase
(JNK)
[84]
Caffeicacid
phenethyleste
rPh
enoliccompo
und
6-OHDA-indu
cedratP
Dmod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3andcaspase-9
cytochromec
release
Maintenance
ofmito
chon
drialintegrityandfunctio
n
[85]
Prim
arycultu
reso
fcerebellarg
ranu
leneuron
6-OHDA-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway,
caspase-3
cytochromec
release
[86]
CNB-001
Pyrazolederiv
ativeo
fcurcum
in
MPT
P-indu
cedrodent
PDmod
elMaintenance
ofno
rmalmito
chon
drialm
orph
ologyandsiz
e[87]
Invitro
human
neurob
lasto
maS
K-N-SHcells
mod
elof
roteno
ne-in
ducedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-3andcaspase-9
cytochromec
release
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
l
[88]
-
Oxidative Medicine and Cellular Longevity 7
Table1:Con
tinued.
Com
poun
dClasso
fcom
poun
dParkinsons
mod
elMechanism
sRe
ferences
Curcum
inPo
lyph
enol
PC12
cells
mutantA
53T-synuclein-in
ducedcelldeath
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3andcaspase-9
cytochromec
release
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
n
[89]
Mou
sebrainandthe1RB
3AN27
(N27)ratdo
paminergic
neuron
alcelllin
emod
elof
buthionine
sulfo
ximine-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:activ
ities
ofcomplex
Ioxidatived
amagetoproteins
glutathion
e
[90]
DL-3-n-
butylphthalid
e(N
BP)
Synthetic
compo
und
basedon
L-3-n-bu
tylphthalid
e
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
elof
MPP
(+)-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
nglutathion
e
[91]
Echinacosid
ePh
enylethano
idglycoside
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
elof
H2O
2-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway
[92]
Edaravon
ePy
razolederiv
ative
Roteno
ne-in
ducedratP
Dmod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Ba
xMaintenance
ofmito
chon
drialintegrityandfunctio
n:RO
Sgeneratio
n
[93]
Esculetin
Cou
marin
MPT
P-indu
cedmiceP
Dmod
elInhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3
[94]
Ginseno
sideR
ePanaxatriolsapon
inPINK1
nullcells
Reversingthed
eficitincomplex
IVactiv
ity:
LR
PPRC
,Hsp90,and
Hsp60
levels
[95]
Glutamoyld
ieste
rof
curcum
inPo
lyph
enol
Mou
sebrainmito
chon
driaindu
ced-peroxynitrite
PDMaintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
n[96]
Harmalol
Beta-carbo
line
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
elof
SNAP-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
n[97]
Harmine
Beta-carbo
line
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
elof
SNAP-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
n[97]
Hesperid
inPo
lyph
enol
Invitro
human
neurob
lasto
maS
K-N-SHcells
mod
elof
roteno
ne-in
ducedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-3andcaspase-9
cytochromec
release
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
nglutathion
e
[98]
-
8 Oxidative Medicine and Cellular Longevity
Table1:Con
tinued.
Com
poun
dClasso
fcom
poun
dParkinsons
mod
elMechanism
sRe
ferences
Isob
orneol
Mon
oterpeno
idalcoho
lIn
vitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
elof
6-OHDA-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-3
cytochromec
release
[99]
Kaem
pferol
Flavon
oid
Invitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
eland
prim
aryneuron
sofrotenon
e-indu
cedPD
Au
toph
agy
[100]
-Lipoica
cid
Organosulfur
compo
undderiv
edfro
moctano
icacid
Invitro
ratadrenalph
eochromocytom
aPC12cells
mod
elof
MPP
(+)-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
n[75]
Roteno
ne-in
ducedratP
Dmod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialcom
plex
Iactivity
glutathion
e[76]
Invitro
human
neurob
lasto
maS
K-N-M
Ccells
mod
elof
roteno
ne-in
ducedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialbiogenesis
RO
Sgeneratio
n[77]
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
elof
PD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialcom
plex
Iactivity
glutathion
e[78]
Lycopene
Caroteno
id
Invitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
elof
MPP
(+)-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
nlip
idperoxidatio
nintracellularA
TPprod
uctio
nmito
chon
drialD
NAcopy
numbersandmito
chon
drialR
NA
transcrip
tlevels
[101]
Roteno
ne-in
ducedratP
Dmod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
cytochromec
release
Maintenance
ofmito
chon
drialintegrityandfunctio
n:lip
idperoxidatio
nSO
Dactiv
ityglutathion
e
[102]
MPT
P-indu
cedmiceP
Dmod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lantio
xidant
enzymelevels
intracellularA
TPprod
uctio
n
[67]
Roteno
ne-in
ducedratP
Dmod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:RO
Sgeneratio
nglutathion
eSO
Dandcatalase
activ
ities
[68]
-
Oxidative Medicine and Cellular Longevity 9
Table1:Con
tinued.
Com
poun
dClasso
fcom
poun
dParkinsons
mod
elMechanism
sRe
ferences
Melaton
inHormon
eRo
teno
ne-in
ducediso
latedratb
rain
mito
chon
driaPD
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:Ca
2+levels
RO
Sgeneratio
n[69]
6-OHDA-indu
cedratP
Dmod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialcom
plex
Iactivity
[70]
MPP
(+)-indu
cediso
latedratliver
mito
chon
driaandstr
iatal
synaptosom
esPD
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialcom
plex
Iactivity
[71]
Mito
Q(m
itoqu
inon
emesylate)
In
vitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
elof
6-OHDA-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Ba
xDrp1
[73]
N-Acetylcysteine
Aminoacid
deriv
ativeH
2O2andtoxicq
uino
nesd
erived
from
dopamine-indu
cedrat
PDmod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialrespiratory
activ
ityNa+
,K+-AT
Pase
activ
ity[103]
Neuropeptidec
ocaine
andam
phetam
ine
regulatedtranscrip
t(C
ART
)
Peptide
Invitro
human
neurob
lasto
maS
H-SY5
Y,HEK
293cells,and
cultu
reso
fcorticalandhipp
ocam
paln
eurons
ofH
2O2-indu
ced
PD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:protectio
nof
mito
chon
drialD
NA(m
tDNA),cellu
larp
roteins,
andlip
ids
[78]
Osth
ole
Cou
marin
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
elof
MPP
(+)-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-3
cytochromec
release
[104]
Piperin
eAlkaloid
6-OHDA-indu
cedratP
Dmod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-3andcaspase-9
cytochromec
release
[105]
Polyhydroxylated
fullerene
deriv
ative
C(60)(OH)(24)
In
vitro
human
neuroblasto
mac
ellsmod
elof
MPP
(+)-indu
ced
PD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
nactiv
ities
ofcomplexes
Iand
IIoxidatived
amagetoDNAandproteins
[106]
Protocatechu
icacid
Polyph
enol
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
elof
MPP
(+)-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2caspase-3
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
nglutathion
e
[107]
-
10 Oxidative Medicine and Cellular Longevity
Table1:Con
tinued.
Com
poun
dClasso
fcom
poun
dParkinsons
mod
elMechanism
sRe
ferences
Pyruvate
Organicacid
Invitro
human
neurob
lasto
maS
K-N-SHcells
mod
elof
H2O
2-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
n[79]
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
elof
dopamine-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
np53
nu
clear
translo
catio
nof
NF-kapp
aBInhibitio
nof
them
itochon
drialapo
ptoticpathway
[80]
Quercetin
Biofl
avon
oid
Roteno
ne-in
ducedratP
Dmod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:RO
Sgeneratio
nmaintainmito
chon
drialm
embranep
otentia
l[108]
Invitro
glial-n
euronalsystem
mod
elof
MPP
(+)-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:indu
ciblen
itricoxides
ynthasep
rotein
expressio
nsuperoxide
radicals
[109]
Rapamycin
Macrolid
e6-OHDA-indu
cedratP
Dmod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-9
cytochromec
release
Maintenance
ofmito
chon
drialintegrityandfunctio
n:lip
idperoxidatio
nSO
DandGSH
-PX
[110]
Resveratrol
Polyph
enol
Invitro
prim
aryfib
roblastscultu
resfrom
patientsw
ithparkin
mutations
(PARK
2)
Maintenance
ofmito
chon
drialintegrityandfunctio
n:complex
Iactivity
citrates
ynthasea
ctivity
basaloxygenconsum
ption
mito
chon
drialA
TPprod
uctio
nlactatec
ontent
[111]
Rosm
arinicacid
Polyph
enol
Invitro
MES
23.5do
paminergicc
ellsmod
elof
6-OHDA-indu
cedPD
.
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
n[112]
Salvianica
cidA
Polyph
enol
Invitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
elof
MPP
(+)-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
x[113]
Salviano
licacid
BPo
lyph
enol
Invitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
elof
6-OHDA-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-3
cytochromec
release
[114]
-
Oxidative Medicine and Cellular Longevity 11
Table1:Con
tinued.
Com
poun
dClasso
fcom
poun
dParkinsons
mod
elMechanism
sRe
ferences
Sesamin
Lign
anIn
vitro
glial-n
euronalsystem
mod
elof
MPP
(+)-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:indu
ciblen
itricoxides
ynthasep
rotein
expressio
nsuperoxide
radicals
[22]
Tetram
ethylpyrazine
Pyrazine
MPT
P-indu
cedratP
Dmod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-3
cytochromec
release
[115]
Tyrosol
Phenoliccompo
und
MPP
(+)-indu
cedCA
TH.acells
PDmod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
l;maintainintracellularA
TPprod
uctio
nInhibitio
nof
them
itochon
drialapo
ptoticpathway:
(i)activ
ationof
PI3K
/Akt
signalling
pathway
[116]
Umbelliferone
Cou
marin
MPT
P-indu
cedmiceP
Dmod
elInhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3
[94]
Ursod
eoxycholic
acid
Second
arybileacids
Invitro
human
neurob
lasto
maS
H-SY5
Ycells
mod
elof
SNP-indu
cedPD
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2Ba
xcaspase-3,caspase-7,andcaspase-9
cytochromec
release
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
nglutathion
e
[74]
XyloketalB
Triterpenoid
Invitro
ratadrenalph
eochromocytom
a(PC
12)cellsmod
eland
Caenorhabditiseleg
anso
fMPP
(+)-indu
cedPD
Maintenance
ofmito
chon
drialintegrityandfunctio
n:maintainmito
chon
drialm
embranep
otentia
lRO
Sgeneratio
nglutathion
e
[117]
-
12 Oxidative Medicine and Cellular Longevity
signaling pathway and by maintaining ATP production
andmitochondria membrane potential [116]. The caffeic acidphenethyl
ester inhibited 6-OHDA-induced mitochondrialapoptotic pathway in in
vitro and in vivomodels [85, 86].Thecurcumin polyphenol derived
from the spice turmeric acts asmitochondrial antiapoptotic agent
through the inhibition ofcaspase-3 and caspase-9 activities and
cytochrome c releaseand it also protects mitochondrial integrity
and function viaROS production inhibition and complex I activity
enhance-ment [89, 90]. In addition to curcumin, its synthetic
pyra-zole derivative compound, CNB-001, has been also studied,which
avoids rotenone-inducedmitochondrial damage in thehuman
neuroblastoma SK-N-SH cells by inhibiting mito-chondrial apoptotic
pathway and maintaining mitochondrialstructure [87, 88]. Glutamoyl
diester of curcumin has alsobeen shown to maintain mitochondrial
membrane potentialand to inhibit ROS production in mouse brain
mitochon-dria induced-peroxynitrite Parkinsons disease model
[96].Salvianic acid A and salvianolic acid B isolated from
Salviaspp. as well as protocatechuic acid afford in vitro
protectionthrough antiapoptotic pathway [107, 113, 114]. The
flavonoidkaempferol exerts antiparkinsonian effect via
autophagy[100] and rosmarinic acid maintains mitochondria
protec-tion by maintaining mitochondrial membrane potential
anddecreasing ROS production [112].
Other natural products with mitochondrial protectiveeffect are
the coumarins umbelliferone, esculetin, and ostholewhich in in
vitro and in vivo Parkinsons disease modelshave been demonstrated
to possess antiapoptotic propertieson mitochondria [94, 104]. Other
compounds that exertprotection via inhibition of the mitochondrial
apoptoticpathway are the monoterpenoid alcohol isoborneol [99],the
alkaloid piperine [105], the pyrazine tetramethylpyrazine[81], and
the nonprovitamin A carotenoid astaxanthin [115].On the other hand,
the -carboline alkaloids harmalol andharmine maintained
mitochondria membrane potential anddecreased ROS generation in PC12
cells exposed to S-nitroso-N-acetyl-DL-penicillamine (SNAP) [97].
Moreover,the triterpenoid xyloketal B also maintained mitochon-dria
membrane potential and decreased ROS generationand it increased
glutathione levels in in vitro rat adrenalpheochromocytoma (PC12)
cells and Caenorhabditis elegansof MPP(+)-induced PD [117].
Furthermore, the carotenoidlycopene inhibited macromolecular
mitochondrial damage(lipids, DNA, and proteins), overproduction of
ROS, ATPfailed production, and cytochrome c release in
MPP(+)-induced human neuroblastoma SK-N-SH cells and
rotenone-induced rat model [101, 102].
3. Alzheimers Disease and Mitochondrial-Targeted Protective
Compounds
3.1. Alzheimers Disease. Alzheimers disease (AD) is a
neu-rodegenerative disease characterized by progressive
cognitivedecline leading to complete need for care within several
yearsafter clinical diagnosis [124]. AD is the most common formof
dementia, being the most prevalent neurodegenerativedisease
(followed by Parkinsons disease), and accounts for
approximately 65% to 75% of all dementia cases. It has
beenestimated that Alzheimers disease affects over 44 millionpeople
worldwide, mainly after the age of 65 years [125, 126].The
incidence of AD augments with age in an exponentialmanner and its
prevalence increases from 3% among indi-viduals aged 6574 to almost
50% among those 85 or older;these numbers can be translated to the
extremely high healthcare costs thatAD represents [127]. In
addition, because of theaging of the population, it is expected
that the prevalence willquadruple by 2050, which means 1 in 85
persons worldwidewill be living with the disease [128].
AD is a progressive neurodegenerative disease with amarked late
onset (late diagnosis as well) and mainly charac-terized by
progressive decline of cognitive functions, mem-ory, and changes in
behavior and personality [129, 130].The two major
pathophysiological hallmarks that have beenobserved in postmortem
brains of AD patients include extra-cellular -amyloid protein (A)
deposits in the form of senileplaques and intracellular deposition
of the microtubule-associated protein tau as neurofibrillary
tangles, especiallyabundant in the regions of the brain responsible
for learningand memory. These features have been linked to an
abnor-mally enhanced neuronal loss in this condition,
especiallyaffecting cholinergic neurons and consequently leading to
areduction in the levels of the neurotransmitter acetylcholinein
the hippocampus and cortex areas of brains of ADpatients. Moreover,
AD has also been associated with theloss of synapses, synaptic
function, inflammatory responsesinvolving glial cells, and
mitochondrial abnormalities [131133].
Considering AD pathogenesis, multiple etiological fac-tors
including genetics, environmental factors, diet, andgeneral
lifestyles have to be taken into account [134]. Most ofthe cases of
AD are believed to be sporadic and their causalfactors are still
unknown for the vast majority of patients;on the other hand,
genetic factors cause about 2% of all ADcases and include mutations
in APP (A protein precursor),presenilin-1 and presenilin-2 genes,
and polymorphisms inapolipoprotein allele E4 [135, 136].
Due to the complex and not fully understood etiopathol-ogy of
AD, no available drug has been shown to completelyprotect neurons
in AD patients, and there is a continuoussearch for new compounds
and therapeutic tools. Thereare two possible conceptual approaches
to the treatment ofAD. The first one is a symptomatic treatment
that tries tominimize tertiary cognitive symptoms and protects
fromfurther cognitive decline; it is the most common
therapeutictendency and drugs such as tacrine, donepezil, and
rivastig-mine have been used with this purpose with limited
efficacy.Another approach is the treatment addressed to prevent
theonset of the disease by sequestering the primary progenitorsor
targets, to reduce the secondary pathologies of the disease,to slow
disease progression, or to delay onset of disease, bypreventing or
attenuating neuronal damaging factors [137,138]. With regard to
this, compounds that exert activityagainst oxidative stress
andmitochondrial dysfunction inAD(as discussed below) deserve to be
considered as potentialtherapeutic options.
-
Oxidative Medicine and Cellular Longevity 13
During the last two decades, consistent evidences haveproposed
oxidative stress as a crucial pathogenic mechanismunderlying AD
[139]. Oxidative stress (OS) occurs whenthe production of reactive
oxygen species (ROS) exceedsthe antioxidant enzymatic and
nonenzymatic cellular mech-anisms. Actually, the -amyloid peptide
A
142 (insolubleform), which forms the senile plaques, exerts
neurotoxicityinvolving OS in AD. Particularly, this A
142 has the abilityto produce ROS, mainly hydrogen peroxide,
when it reactswith transition metal ions present in senile plaques
[140].As a result of OS, accumulated oxidative damage to
lipids,proteins, and nucleic acids in postmortem studies of
brainsof patients with AD has been identified: advanced
glycationend-products (AGEs), advanced lipid peroxidation
end-products, nucleic acid oxidation, carbonyl-modified
neuro-filament protein, and free carbonyls [141]. The brain ismore
susceptible to OS than other organs because of a lowantioxidative
protection system, which allows for increasedexposure of target
molecules to ROS; the higher level of ROS,together with
neuroinflammation and excessive glutamatelevels, is proposed to
contribute to neuronal damage anddeath in AD [142].
3.1.1.Mitochondrial Dysfunction inAD. Mitochondria are
theprimary source of ROS, and oxidative damage to mitochon-drial
components precedes damage to any other cellular com-ponent during
the development of neurodegenerative dis-eases [143]. Actually,
mitochondrial dysfunction has largelybeen demonstrated as one of
the main key cytopathologiesof AD [144, 145]. Numerous evidences
suggest the involve-ment of -amyloid protein deposits in the
mitochondrialdysfunction found in AD as a plausible mechanism for
itsneurodegenerative effects [146148]. In support of this, it
hasbeen shown that cells depleted of endogenousmDNA
lackingfunctional electron transport chains (ETC) are resistant toA
toxicity [149]; also, a reduced respiratory capacity andlow
cytochrome oxidase activity were found in isolatedmitochondria
exposed to A [150, 151]; transgenic miceexpressing mutant APP
(amyloid protein precursor) genesexhibit mitochondrial dysfunction,
and an AD transgenicmouse line presents early expression of genes
encodingmito-chondrial proteins and ETC subunits, as an initial
cellularchange in AD pathology [152].
Mitochondria have been shown to be a direct site ofA
accumulation in AD neurons, and various experimentalmodels of AD
were used by researchers to verify the effectof that specific
accumulation on cell death [153]. Actually,Manczak et al. proved an
association between mutant APPderivatives (A monomers and
oligomers, such as A
140and A
142) and mitochondria in cerebral cortex slices fromTg2576 mice
and N2a cells expressing mutant APP. Suchaccumulation supposes an
increase in mitochondrial ROSproduction together with a reduced Cyt
C oxidase activity,thus relating in vivo oxidative stress and
impaired mitochon-drial metabolism to the toxic effects of A
peptides [154].Further, Devi et al. demonstrated that the
mitochondrialdysfunction in human AD brain is associated with
theabnormal accumulation of APP across the mitochondrial
import channels. In postmortem evaluations, it was evidencedthat
nonglycosylated full-length and C-terminal truncatedAPP had been
accumulated exclusively in the protein importchannel of
mitochondria of AD brains (specially higheraccumulation in
AD-vulnerable regions, such as cortex,hippocampus, and amygdala),
by forming stable complexeswith the outer membrane translocase
and/or the inner mem-brane translocase; the effect of such
association could inhibitthe entry of nuclear encoded Cyt C oxidase
protein, thusdiminishing its activity in mitochondria and
increasing thelevels of H
2O2.The higher the level of arrestedmitochondrial
APP, the worse the mitochondrial dysfunction [155].What ismore,
a recent study indicated thatmitochondria-
targeted A142 accumulation is the necessary and sufficient
condition for A-mediated mitochondrial impairments andderived
cellular death. In an in vitromodel ofmice hippocam-pal cell line
(HT22 cells), an exogenous A
142 treatmentcaused a deleterious alteration in mitochondrial
morphologyand function, which was blocked by a
clathrin-mediatedendocytosis blocker; besides, specific
mitochondria-targetedaccumulation of A
142 in HT22 cells using a mitochondria-targeting sequence
reproduced the same morphological andfunctional alterations of
mitochondria as those observed inAPP mutant mice model and the
previous A
142-treatedHT22 cells. Mitochondria-mediated apoptotic cell
deathwas observed in both models, thus implying that no
othersignaling alteration induced by A plays a more relevant rolein
cell death than its mitochondrial toxicity [156].
In general, mitochondrial dysfunction in AD is essen-tially
characterized by diminution in complex IV activity(cytochrome c
oxidase), decline in other enzymes of tricar-boxylic acids cycle,
andmutations tomDNA.Themechanismthat underlies the complex IV
defect is not clearly known,but a study on SK-N-SH cells exposed to
A-inducedtoxicity showed a decrease in mDNA encoded complexIV
subunits, at both the mRNA and protein levels; thisfinding suggests
a possible relationship between decreasedcomplex IV activity and
mDNA perturbation [157]. Resultsfrom cybrids studies also imply
that AD is characterizedby specific mDNA mutations that correlate
with defects incertain mitochondrial respiratory complexes. These
changesgenerate an increased production of oxidant species and
freeradicals, such as hydrogen peroxide. In turn, a deficiencyin
energy metabolism and ATP generation is a seriousconsequence of
impaired mitochondrial function [158, 159].In addition, deficiency
in scavenging mitochondrial freeradicals may similarly contribute
to the excessive oxidativedamage in the affected brain regions in
AD. For instance,decreased mitochondrial MnSOD expression level has
beenfound in AD patients as well as decreased Coenzyme Qin
peripheral tissues and brains [160, 161]. Therefore, arelationship
between the mitochondrial dysfunction and theoxidative stress
situation is established.
Neurodegeneration and synaptic degradation in AD areprimarily
mediated by defective mitochondrial biogenesisand axonal transport
of mitochondria [162]. Normal mito-chondrial dynamics, an essential
function inmaintaining cellviability, is likewise impaired in AD.
Disturbances affectingthe balance of fusion and fission processes
trigger serious
-
14 Oxidative Medicine and Cellular Longevity
mitochondrial changes and lead to cellular perturbations,such as
apoptosis. Recent studies have found altered levelsof mitochondrial
fusion (including MNF-1/2 and OPA1) andfission (FIS1) proteins in
AD hippocampal tissues, meaningdecreased fusion and increased
fission processes; mitochon-drial fission proteinDLP1 has also been
found to be decreasedin hippocampal neurons [163]. Moreover,
mitochondrial cal-cium overload is another feature of mitochondrial
dysfunc-tion inAD;Ahas been shown to cause calciumoverload thatthen
causes increased free radical accumulation and provokesthe
formation of mitochondrial transition pore (mPTP), thusleading to
exacerbation of cytoplasmic calcium and eventualneuronal death
[164].
Further, mitochondria play a pivotal role in aging
andsenescence, contributing to neural dysfunction with age.They are
actually the main cellular organelle implicated inthe process of
neuronal apoptosis, which takes place in anexcessive manner in AD
brains [165]. The fact that manyneurons undergo apoptosis in AD is
evidenced by the pres-ence of high levels of activated proapoptotic
proteins suchas caspase-3 and Bax in neurons that exhibit
neurofibrillarytangle pathology [166].
Concerning AD models of study, unfortunately, there isno animal
model so far that replicates all the major aspectsof AD pathology
and symptoms, andmodels based on postu-lated disease pathways are
widely used to explore biologicaltargets [167]. Regarding the
investigation of the effects ofcompounds onmitochondrial
dysfunction, rodent transgenicmodels are very common for
reproducing the mitochon-driopathy features in AD. For instance, an
APP (amyloidprecursor protein) mice transgenic model demonstratedan
accelerated upregulation of the apoptotic-related factorsinvolved
in mitochondria-mediated apoptosis, such as Baxand caspase-3 [168].
Similarly, isolated mitochondria fromAPPSW mice (expressing the
Swedish familial mutation inAPP gene) presented an abnormally
reduced mitochondrialrespiratory rate, mitochondrial membrane
potential (MMP)disruption, increased ROS generation, and lower ATP
levels[169]. APP/PS1 transgenic mice include mutations both inAPP
and in presenilin-1 genes and show similar mitochon-drial
characteristics [170]. Other models even express moremutations,
such as 3xTg-ADmousemodel that includes threemutant human genes:
APPswe, presenilin-1 (PS1M146V), andtau protein (tau P301L); in
this model, MMP loss and highercaspases 3 and 9 activations are
observed [171].
However, most of the works assessing mitochondrialdefects in AD
are still performed on toxin-induced invitro models. With this
respect, rat primary neurons inculture exposed to A
142 oligomers reproduced the gen-eration of mPTP in
mitochondrial membrane with sub-sequent calcium overload, the MMP
loss, and release ofcytochrome C, thus leading to cell death via
mitochondrial-mediated apoptosis [172]. Mouse neuroblastoma N2a
cellscotransfected with Swedish mutant APP and 9
deletedpresenilin-1 (N2a/Swe.9) recapitulated similar loss of
mito-chondrial integrity and function and evidenced
increasedmitochondrial apoptotic pathway, with a higher
Bax/Bcl2ratio and augmented caspase-3 activity [173]. Recent
studieshave employed cybrid neurons resulting from
incorporating
platelet mitochondria from AD patients into
mitochondrialDNA-depleted neuronal cells (SH-SY5Y cell line); this
modeldemonstrates changes in length and density of mitochon-dria,
imbalanced mitochondrial fission, and fusion dynamics(altered
expression and distribution of DLP1 and Mfn2proteins), together
with reduced mitochondrial function andenergy metabolism [174].
Therefore, it has been suggested that a substance of exoge-nous
or endogenous origin that is able to reverse any of
theaforementioned mitochondrial deficits may facilitate a
betterneuronal health and then be of interest of study as a
potentialactive compound in AD therapy [175]. In fact,
mitochondrialmedicine is emerging as a field of research focused on
thefinding of therapeutic strategies to enhance
mitochondrialfunction in aging and in those neurodegenerative
diseasesin which it has been shown to be impaired [176178].
Thisavenue of investigation has led to the discovery of
severalagents directly targeted to mitochondria that are able to
delayor revert themitochondrial impairments associated toAD;
allavailable information on these compounds is reviewed belowand
collected in Table 2 and schematized in Figure 3.
3.2. Mitochondria-Targeted Protective Compounds in AD
3.2.1. Synthetic Compounds. Several
mitochondria-targetedantioxidants have been designed by conjugating
the lipophilictriphenylphosphonium (TPP+) cation to an
antioxidantmoiety, such as coenzyme Q (CoQ), obtaining as a
resultcompounds like MitoQ [219]. Due to its chemical nature,MitoQ
takes advantage of the large MMP for reaching highconcentrations in
mitochondria and, unlike isolated CoQ,it is an effective
antioxidant in the absence of functionalETC [220, 221]. McManus et
al. demonstrated that MitoQ iseffective in preventing loss of
spatial memory and delayingthe early neuropathology in a triple
transgenic mouse modelof AD; they evaluated its effect on
mitochondrial deficiencyand found that MitoQ avoided the MMP drop
and reducedthe apoptosis in cortical neurons by a decrease in
caspase-3 activity [171]. Another study employed a
Caenorhabditiselegansmodel overexpressing human A end evidenced
thatMitoQ exerted protective effects on lifespan and
A-inducedparalysis and markedly ameliorated the depletion of
mito-chondrial lipid cardiolipin and increased the mitochondrialETC
function by protecting complexes IV and I; however, itwas not able
to reduce the A-induced mitochondrial DNAoxidative damage
[201].
Recently, Szeto developed a series of small, cell-perme-able
antioxidant peptides (SS peptides) that are known toprotect
mitochondria from oxidative damage [222]. SS31
(H-D-Arg-Dmt-Lys-Phe-NH2) is one of them and presents asequence
motif that allows it to target mitochondria. In anA2535-induced AD
model of mice hippocampal neurons,
SS31 restored axonal transport ofmitochondria and
displayedpromising protection and maintenance of
mitochondrialfunction, proved by an increase in the number of
healthy andintact mitochondria and a reduction in the levels of
fissionproteins, matrix protein, andCypD [162]. Similar results
werefound by Calkins et al. [211]. Manczak et al. also revealed
-
Oxidative Medicine and Cellular Longevity 15
Table2:Alzh
eimersdiseasea
ndmito
chon
dria-ta
rgeted
protectiv
ecom
poun
ds.
Com
poun
dClasso
fcom
poun
dADmod
elMechanism
/effect
References
17--Estr
adiol
Estro
gen
Invitro
isolatedmito
chon
driafro
mpostm
ortem
human
ADand
SFADbrains
Activ
ationof
mito
chon
drialaconitase
[179]
Acetyl-L-carnitin
eAminoacid
Invivo
F344
ratm
odel
Resto
ratio
nof
intactmito
chon
drialm
orph
ologyand
preventio
nfro
mage-relatedmito
chon
driald
ecay
[180]
Acteoside
Glycosid
eIn
vitro
A2535-in
ducedSH
-SY5
Yhu
man
neuroblasto
mac
ells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:RO
Sprod
uctio
nMMPloss
Cy
tCrelease
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Ba
x/Bc
l-2ratio
caspase-3cle
avage
[181]
ASS234
Aminew
ithcomplex
structure
Invitro
A142-in
ducedSH
-SY5
Yhu
man
neuroblasto
mac
ells
mod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
levelsof
cleaved
caspases
3and9
levelsof
proteolysedPA
RP[182]
Caffeine
Alkaloid
Invivo
APP
swmicem
odel
Maintenance
ofmito
chon
drialintegrityandfunctio
n:resto
ratio
nof
mito
chon
drialrespiratory
rate,
maintenance
ofMMP
RO
Sprod
uctio
nAT
Plevels
[169]
Colostrinin
Polypeptide
Invitro
A-in
ducedhu
man
SH-SY5
YandratP
C12cells
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialH
2O2prod
uctio
n[183]
Crud
ecaffeine
Alkaloid
Invitro
prim
aryneuron
sfrom
J20mou
selin
e
Maintenance
ofmito
chon
drialintegrityandfunctio
n:AT
Plevels
RO
Sprod
uctio
nInhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3activ
ity
[184]
Cyclo
sporin
A
Invitro
isolatedcorticalmito
chon
driafro
mmAPP
-Ppif
/transgenicmice
Maintenance
ofmito
chon
drialintegrityandfunctio
n:inhibitio
nof
mPT
Pop
ening
Ca
2+bu
fferin
gcapacity
[185]
D609
Tricyclodecan-9-yl-
xantho
genate
Invitro
A142-in
ducediso
latedbrainmito
chon
driamod
el(fr
omgerbils)
Maintenance
ofmito
chon
drialintegrityandfunctio
n:levelsof
proteincarbon
yls
levelsof
protein-bo
undHNE
levelsof
3-NT
Cy
tCrelease
Maintenance
ofGSH
/GSSGratio
GST,G
Px,and
GRactiv
ities
[186]
DAPT
Com
plex
structure
ofbu
tyleste
rIn
vitro
N2a/A
PP695andN2a/A
PPsw
ecellsmod
elsMaintenance
ofmito
chon
drialintegrityandfunctio
n:stabilizatio
nof
norm
alMMPandAT
Plevels
[187]
Dim
ebon
Tetrahydrocarboline
Invitro
A2535-exposed
isolatedratb
rain
mito
chon
dria
Maintenance
ofmito
chon
drialintegrityandfunctio
n:inhibitio
nof
mPT
Pop
ening
[188]
-
16 Oxidative Medicine and Cellular Longevity
Table2:Con
tinued.
Com
poun
dClasso
fcom
poun
dADmod
elMechanism
/effect
References
Edaravon
ePy
razolin
one
Invitro
N2a/Swe.
9cells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n,MMP
RO
Sprod
uctio
nCy
tCrelease
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Ba
x/Bc
l2ratio
Ca
spase-3activ
ation
[173]
Ergothioneine
2-Mercaptoh
istidine
trim
ethylbetaine
Invitro
A2535-in
ducedPC
12ratp
heochrom
ocytom
acells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:MMPloss
Inhibitio
nof
them
itochon
drialapo
ptoticpathway,
ratio
Bax/Bc
l-XL
caspase-3activ
ation
[189]
Gels
olin
Peptide
Invitro
A142-in
ducedratepithelialcells
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:increase
inmito
chon
drialcom
plex
IVactiv
ity[19
0]
Genistein
Phytoestrogen
Mito
chon
drialfractionof
postm
ortem
human
ADbrains
mito
chon
drialN
a/K-AT
Pase
activ
ity[191]
GLP
-1(9-36)
amide
Peptide
Invitro
sliceso
fhippo
campu
sfrom
APP
/PS1
mice
Maintenance
ofmito
chon
drialintegrityandfunctio
n:abno
rmalmito
chon
drialSOlevels
[192]
Glutathione
Tripeptid
eIn
vitro
A-in
ducedhu
man
HCN
-1Acells
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialm
embraned
epolarization
[193]
Invitro
isolatedmito
chon
driafro
mpostm
ortem
human
ADand
SFADbrains
Activ
ationof
mito
chon
drialaconitase
[179]
GypenosideX
VII
Phytoestrogen
Invitro
A2535-in
ducedPC
12cells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:resto
ratio
nof
norm
alMMP
Cy
tCrelease
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3activ
ationandcle
avage
PA
RPcle
avage
[194]
JHX-
4,HK-
2,and
HK-
4
Invitro
A-in
ducedhu
man
SH-SY5
Ycells
mod
elPreventio
nfro
mMnC
l 2-indu
cedlossof
mito
chon
drialactivity
[195]
Lipo
icacid
Organosulfur
compo
undderiv
edfro
moctano
icacid
Invivo
F344
ratm
odel
Resto
ratio
nof
intactmito
chon
drialm
orph
ologyand
preventio
nfro
mage-relatedmito
chon
driald
ecay
[180]
Invitro
fibroblastsfro
mADpatients
Maintenance
ofmito
chon
drialintegrityandfunctio
n:NMP-indu
cedmito
chon
drialoxidativ
estre
ssInhibitio
nof
them
itochon
drialapo
ptoticpathway:
Ba
xandcaspase-9levels
[196]
-
Oxidative Medicine and Cellular Longevity 17
Table2:Con
tinued.
Com
poun
dClasso
fcom
poun
dADmod
elMechanism
/effect
References
Invitro
A2535-indu
cedmou
semicroglialB
V2cells
mod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
activ
ationof
Bcl-2
antiapo
ptoticpathways
Ba
xmRN
Alevel
Bc
l-2expressio
ncaspase-3activ
ity
[197]
Invitro
A2535-indu
cedrath
ippo
campaln
eurons
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:resto
ratio
nof
MMPloss
attenu
ationof
respira
tory
chaincomplexes
AT
Plevels
[198]
Melaton
inHormon
eIn
vivo
APP
/PS1
transgenicmice
Maintenance
ofmito
chon
drialintegrityandfunctio
n:resto
ratio
nof
mito
chon
drialrespiratory
rates
MMP
AT
Plevels
[170]
Invivo
APP
swmicem
odel
Maintenance
ofmito
chon
drialintegrityandfunctio
n,resto
ratio
nof
mito
chon
drialrespiratory
rate
maintenance
ofMMP
RO
Sprod
uctio
nAT
Plevels
[169]
Invitro
isolatedmito
chon
driafro
mpostm
ortem
human
ADand
SFADbrains
Activ
ationof
mito
chon
drialaconitase
[179]
Invivo
APP
transgenicmicem
odel
Maintenance
ofmito
chon
drialintegrityandfunctio
n,SO
Dactiv
ityInhibitio
nof
them
itochon
drialapo
ptoticpathway,
Ba
x,caspase-3,andPar-4expressio
ns
[168]
Methylene
blue
Phenothiazine
Invivo
C57B
L/6mice
Maintenance
ofmito
chon
drialintegrityandfunctio
n,mito
chon
drialcom
plex
IV(CytCoxidase)
activ
ityMAO
activ
ity
[199]
Invitro
A-in
ducedmou
seneurob
lasto
maN
2acells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n,abno
rmalexpressio
nof
peroxiredo
xins
and
mito
chon
drialstructuralgenes
norm
alizationin
mito
chon
drianu
mber
[200]
Mito
QMethanesulfo
nate
Invivo
APP
transgenicmice
Maintenance
ofmito
chon
drialintegrityandfunctio
n:Cy
pDexpressio
n
Invivo
3xTg
-ADmice
Maintenance
ofmito
chon
drialintegrityandfunctio
n:preventio
nof
MMPloss
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
blockage
ofcaspases-3/7
activ
ation
[171]
Invivo
Caenorhabditiseleg
ansm
odeloverexpressin
ghu
man
A
peptides
Maintenance
ofmito
chon
drialintegrityandfunctio
n,depletionof
mito
chon
driallipid
cardiolip
inProtectio
nof
complexes
IVandIo
fthe
ETC
[201]
-
18 Oxidative Medicine and Cellular Longevity
Table2:Con
tinued.
Com
poun
dClasso
fcom
poun
dADmod
elMechanism
/effect
References
Mito
chon
drial
divisio
ninhibitor1
(Mdivi-1)
Quinazolin
one
Invitro
A-in
ducedmou
seBV
-2cells
andprim
arymicroglial
cells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:abno
rmalmito
chon
drialfi
ssion
MMPloss
Cy
tCrelease
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-3activ
ation
[182]
Invitro
cybrid
cells
mod
el(m
tDNA-depleted
neuron
alSH
5Y5Y
cells
transfe
cted
with
plateletmito
chon
driafro
mADpatient)
Maintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialR
OSprod
uctio
nMMP
mito
chon
driallengthanddensity
Cy
tCoxidasea
ctivity
SO
Dactiv
ityAT
Plevels
im
paire
dmito
chon
drialfi
ssionandfusio
ndynamics
[174]
N-Acetylcysteine
Aminoacid
deriv
ative
Invitro-amyloid-indu
cedhu
man
HCN
-1Acells
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialm
embraned
epolarization
[193]
Invivo
APP
/PS-1m
ice
Ameliorationof
energy
levelsandmito
chon
drial-related
proteins
[202]
Invitro
fibroblastsfro
mADpatients
Maintenance
ofmito
chon
drialintegrityandfunctio
n:NMP-indu
cedmito
chon
drialoxidativ
estre
ssInhibitio
nof
them
itochon
drialapo
ptoticpathway:
Ba
xandcaspase-9levels
[196]
Neuregulin
-1Peptide
Invitro
mod
elof
SH-SY5
Yhu
man
neurob
lasto
mac
ells
transfe
cted
with
C-term
inalfragmentsof
APP
Maintenance
ofmito
chon
drialintegrityandfunctio
n:MMPloss
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2expressio
n
[203]
Nicotinam
ide
Amide
Invivo
A142-in
ducedratm
odel
Upregulationof
mito
chon
drialfun
ction
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2levels
Ba
xlevels
[204]
Peroxiredo
xin3
Enzyme
Invivo
APP
transgenicmice(Tg
2576)and
APP
/Prdx3
transgenicmicem
odels
Maintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialD
NAoxidation
activ
ityof
mito
chon
drialcom
plexes
Iand
IV[205]
Peroxiredo
xin6
Enzyme
Invitro
A2535-in
ducedPC
12cells
mod
el
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspases
3and9activ
ation
PA
RPactiv
ation
Bc
l-2andBa
xdysregulations
[206]
-
Oxidative Medicine and Cellular Longevity 19
Table2:Con
tinued.
Com
poun
dClasso
fcom
poun
dADmod
elMechanism
/effect
References
Probucol
In
vitro
cybrid
cells
mod
el(m
tDNA-depleted
neuron
alSH
5Y5Y
cells
transfe
cted
with
plateletmito
chon
driafro
mADpatient)
Maintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialR
OSprod
uctio
nMMP
mito
chon
driallengthanddensity
Cy
tCoxidasea
ctivity
SO
Dactiv
ityAT
Plevels
im
paire
dmito
chon
drialfi
ssionandfusio
ndynamics
[174]
Puerarin
Phytoestrogen
Invivo
A142-in
ducedratm
odel
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspase-9activ
ityandmRN
Alevels
[207]
Invitro
cybridcells
mod
el(m
tDNA-depleted
neuron
alSH
-5Y5
Ycells
transfe
cted
with
plateletmito
chon
driafro
mADpatient)
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Bc
l-2levels
Ba
xexpressio
ncaspase-3activ
ity
[208]
R(+)
andS()
pram
ipexoles
In
vitro
A2535-in
ducedSH
-SY5
Yhu
man
neuroblasto
mac
ells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:inhibitio
nof
mPT
Pop
ening
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
caspases
3and9activ
ations
[209]
Resistin
Adipokinep
rotein
Invitro
mou
seN2a/Swe.
9cells
(N2a
cells
transfe
cted
with
Sw-APP
mutantand
presenilinexon
9deletio
nmutant)
Maintenance
ofmito
chon
drialintegrityandfunctio
n:AT
Plevels
MMP
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
Ba
x/Bc
l2ratio
Cy
tCrelease
caspase-3activ
ation
[210]
Resveratrol
Polyph
enol
Invitro
A-in
ducedmou
seneurob
lasto
maN
2acells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:abno
rmalexpressio
nof
peroxiredo
xins
and
mito
chon
drialstructuralgenes
Normalizationin
mito
chon
drianu
mber
[200]
Invivo
APP
transgenicmice
Maintenance
ofmito
chon
drialintegrityandfunctio
n:Cy
pDexpressio
nSalicylate
Sulin
dacs
ulfid
eIndo
methacin
Ibup
rofen
R-flu
rbiprofen
NSA
IDs
Invitro
A142-a
ndA2535-in
ducedratcerebellarg
ranu
lecells
andcorticalneuron
smod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:MMP
mito
chon
drialC
a2+overload
Cy
tCrelease
[172]
-
20 Oxidative Medicine and Cellular LongevityTa
ble2:Con
tinued.
Com
poun
dClasso
fcom
poun
dADmod
elMechanism
/effect
References
SS31
Peptide
Invitro
A2535-in
ducedC5
7BL/6miceh
ippo
campaln
eurons
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:levelsof
mito
chon
drialfi
ssionproteins
(Drp1,
Fis1),matrix
protein,andCy
pDnu
mbero
fhealth
yandintactmito
chon
dria
Resto
ratio
nof
mito
chon
drialtranspo
rt
[162]
Invitro
A-in
ducedmou
seneurob
lasto
maN
2acells
mod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:abno
rmalexpressio
nof
peroxiredo
xins
and
mito
chon
drialstructuralgenes
Normalizationin
mito
chon
drianu
mber
[200]
Invivo
APP
transgenicmice
Maintenance
ofmito
chon
drialintegrityandfunctio
n:Cy
pDexpressio
n
Invitro
Tg2576
micep
rimaryneuron
sMaintenance
ofmito
chon
drialintegrityandfunctio
n:resto
ratio
nof
mito
chon
drialtranspo
rtpercentage
ofdefectivem
itochon
dria
[211]
Thym
oquino
neBe
nzoq
uino
neIn
vitro
A2535-in
ducedPC
12cells
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:MMP
[212]
Invitro
A142-in
ducedprim
aryratn
eurons
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:MMP
[213]
Tournefolic
acid
BPo
lyph
enol
Invitro2535-in
ducedratcorticalneuron
smod
el
Maintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialC
a2+levels
delay
inCy
tCrelease
Inhibitio
nof
them
itochon
drialapo
ptoticpathway:
tBid
levels
[214]
Trolox
Analogof
vitamin
EIn
vitro
dentateg
ranu
lecells
from
transgenicmou
seADmod
el(Tg2576)
Maintenance
ofmito
chon
drialintegrityandfunctio
n:scavenging
ofmito
chon
drialSO
resto
ratio
nof
Ca2+cle
arance
MMP
[215]
UPF
1and
UPF
17Peptides
Mito
chon
drialfractionof
postm
ortem
human
ADbrains
Mito
chon
drialM
n-SO
Dactiv
ity[191]
Vitamin
CVitamin
Invitro
A-in
ducedhu
man
HCN
-1Acells
mod
elMaintenance
ofmito
chon
drialintegrityandfunctio
n:mito
chon
drialm
embraned
epolarization
[193]
Invivo
5XFA
DKn
ockout-tr
ansgenicmicem
odel
Maintenance
ofmito
chon
drialintegrityandfunctio
n:preventio
nof
abno
rmalmito