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Nutraceuticals and their preventive or potential
therapeuticvalue in Parkinson's disease
Jianfei Chao, Yen Leung, Mingfu Wang, and Raymond Chuen-Chung
Chang
Parkinson's disease (PD) is the second most common aging-related
disorder in theworld, after Alzheimer's disease. It is
characterized by the progressive loss ofdopaminergic neurons in the
substantia nigra pars compacta and other parts of thebrain, leading
to motor impairment, cognitive impairment, and dementia.
Currenttreatmentmethods, such as L-dopa therapy, are focused only
on relieving symptomsand delaying progression of the disease. To
date, there is no known cure for PD,making prevention of PD as
important as ever. More than a decade of researchhas revealed a
number of major risk factors, including oxidative stress
andmitochondrial dysfunction. Moreover, numerous nutraceuticals
have been found totarget and attenuate these risk factors, thereby
preventing or delaying theprogression of PD. These nutraceuticals
include vitamins C, D, E, coenzyme Q10,creatine, unsaturated fatty
acids, sulfur-containing compounds, polyphenols,stilbenes, and
phytoestrogens. This review examines the role of nutraceuticals in
theprevention or delay of PD as well as the mechanisms of action of
nutraceuticals andtheir potential applications as therapeutic
agents, either alone or in combinationwith current treatment
methods. 2012 International Life Sciences Institute
INTRODUCTION
Parkinsons disease (PD) is regarded as the second mostprevalent
aging-related neurodegenerative disorder afterAlzheimers disease
(AD), aecting approximately0.017% of people between the ages of 50
and 59 years,with a median onset age of around 60 years. Aging
isundoubtedly a major risk factor of PD, as the incidence ofPD
jumps to approximately 0.093% in people between theages of 70 and
79 years. In people over 70 years of age, thenumber of men
diagnosed with PD is about 1.5 timeshigher than that of women.1
Environmental toxins and exposure to pesticideshave also been
reported to contribute to PD morbidity.Examples of environmental
toxins include 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),
toluene,carbon disulde, and cyanide,2 while examples of pesti-cides
include paraquat, organophosphates, and rotenone.3
MPTP exposure has been found to induce both loss ofdopaminergic
neurons and clinical parkinsonism. Simi-larly, rotenone and
paraquat, when applied to experi-mental animals, have been found to
induce loss ofdopaminergic neurons and typical parkinsonism.4
Aspotential etiological factors of PD, environmental
Aliations: J Chao is with the Laboratory of Neurodegenerative
Diseases, Department of Anatomy, LKS Faculty of Medicine, The
Universityof Hong Kong, Pokfulam, Hong Kong SAR, China, and the
School of Biological Sciences, Faculty of Science, The University
of Hong Kong,Pokfulam, Hong Kong SAR, China. Y Leung is with the
Laboratory of Neurodegenerative Diseases, Department of Anatomy,
LKS Faculty ofMedicine, The University of Hong Kong, Pokfulam, Hong
Kong SAR, China. M Wang is with the School of Biological Sciences,
Faculty ofScience, The University of Hong Kong, Pokfulam, Hong Kong
SAR, China. RC-C Chang is with the Laboratory of
NeurodegenerativeDiseases, Department of Anatomy, LKS Faculty of
Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR,
China, and theResearch Centre of Heart, Brain, Hormone and Healthy
Aging, LKS Faculty of Medicine, The University of Hong Kong,
Pokfulam, HongKong SAR, China, and the State Key Laboratory of
Brain and Cognitive Sciences, The University of Hong Kong,
Pokfulam, Hong Kong SAR,China.
Correspondence: RC-C Chang, Rm. L1-49, Laboratory Block, Faculty
of Medicine Building, Department of Anatomy, LKS Faculty
ofMedicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong
SAR, China. E-mail: [email protected]. Phone: +852-2819-9127.
Fax:+852-2817-0857.
Key words: dietary supplement, neuroprotection, nutraceuticals,
Parkinson's disease
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Lead Article
doi:10.1111/j.1753-4887.2012.00484.xNutrition Reviews Vol.
70(7):373386 373
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chemicals may interact with gene expression and modu-late
expression of mutated genes in humans.Thus, geneticanalysis of
patients with PD has become an importantresearch theme in PD.
A small percentage of PD cases are attributed tosingle gene
defects. Thus far, genetic studies have identi-ed more than 10
genes that cause familial PD. The func-tions of these genes, along
with associated clinicalfeatures, are listed in Table 1.5,6
PATHOLOGICAL FACTORS ASSOCIATEDWITHPARKINSON'S DISEASE
PD is dened pathologically by the progressive loss
ofdopaminergic neurons in the substantia nigra (SN) parscompacta
accompanied by the presence of intracellularLewy bodies.
Parkinsonism, along with parkinsonian syn-drome, should be
distinguished from PD.Parkinsonism is
a term that refers only to the clinical symptoms of PD,such as
the occurrence of tremors and dementia,but bearsno implication of
disease mechanism, while PD refers tothe pathology described above.
The exact mechanisms ofPD are not yet fully understood, although
several factors,including protein misfolding, oxidative stress, and
mito-chondrial dysfunction, have been reported.
Numerous studies indicate a causal role of misfoldedproteins
such as beta-amyloid anda-synuclein inAD andPD, as misfolding
results in accumulation of the proteineither extra- or
intracellularly.7 If chaperones fail torestore misfolded proteins,
the ubiquitin proteasomesystem and autophagy will subsequently
clear the mis-folded proteins.8 Both mutation and aggregation
ofa-synuclein can cause parkinsonism, but mutation ofa-synuclein is
rarely found in patients with sporadic PD.9
Unique biochemical features of the SN render itmore vulnerable
to oxidative stress when compared with
Table 1 Gene identication in Parkinson's disease.Gene/protein
Clinical features of gene/
protein expressionFunctions of the protein Pathogenic
mutations
SNCA/alpha-synuclein
Early-onset parkinsonism,onset between 40 and 49years of age,
Lewy bodies,dementia
Mainly unknown, possiblysynaptic vesicle tracking
A53T, A30P, and E46K, all ofwhich may promoteaggregation; Lewy
bodyand Alzheimer plaquecomponent; protobrils(toxic)
UCHL1/ubiquitincarboxy-terminalhydrolase 1
Onset between 50 and 59years of age, typical PDvery rare
Removal of polyubiquitin
LRRK2/leucine-richrepeat kinase 2
Onset between 60 and 69years of age, Lewy bodies,Tau pathology,
typical PD
Mainly unknown; foundprimarily in the cytoplasmbut also
associated with theouter mitochondrialmembrane
G2019S, most common inNorth African, Ashkenazim,and Spanish
populations
HTRA2/serineprotease
Typical PD very rare Mainly unknown; primarilylocalized in
theendoplasmic reticulum andmitochondria
PRKN/parkin Early onset, usually before age30, without Lewy
bodies,rarely juvenile, slowprogression
Ubiquitin E3 ligase attachesshort ubiquitin peptidechains to a
range ofproteins, likely to markdegradation
Over 70 mutations identied
PINK1/PTEN-inducedputative kinase 1
Early onset at 3040 years ofage, slow progression,psychiatric
featurescommon
Mitochondrial kinase;modulates mitochondrialdynamics
DJ-1/DJ-1 Early onset at 3040 years ofage, rarely juvenile
Possible a typicalperoxiredoxin, may beinvolved in apoptosis
L166P, M261, and a variety ofother candidates
ATP13A2/lysosomalATPase
Early onset, dementia,pyramidal features,supranuclear gaze
palsy
Mainly unknown; an ATPaselocated in the lysosome
Nonsense mutation found tobe associated with
pallidaldegeneration
GBA/glucocerebrosidase Typical PD Mainly unknown:
primarilylocated in lysosome
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other parts of the brain. In particular, the SN has auniquely
high iron content.Dopamine can be oxidized bymonoamine oxidase B
(MAO-B) to form hydroxyl freeradicals in the presence of ferrous
iron. The combinedeects result in enormous amounts of hydroxyl free
radi-cals, leading to severe damage of the dopaminergicneurons of
the SN. These pathological events suggest thatoxidative stress is
the most important pathological factorfor the initiation and
progression of PD.10
Indeed, the SNs of PD patients have been found toshow elevated
levels of oxidative stress.Youdim and Ried-erer11 reported that
lipid-peroxidation-promoting sub-stances such as ferrous iron are
found in high levels in theSN of postmortem PD brain, concomitant
with decreasedlevels of antioxidants. Similar results were obtained
by astudy investigating the level of hydroxynonenal adducts,which
are products of lipid peroxidation.12 Elevated levelsof lipid
peroxidation have been found in the SN region ofthe brain and in
erythrocytes from blood samples of PDpatients.13
Numerous studies suggest that impairment of mito-chondrial
function is also involved in the pathogenesis ofPD.Mitochondrial
function is closely related to oxidativestress because mitochondria
produce ATP by oxidativephosphorylation. During ATP production,
mitochondriamay produce superoxide radicals as by-products.
Defectsof the electron transport chain can result in the failureof
energy metabolism, increased free-radical-mediateddamage, and
activation of downstream cell deathpathways.1416 In the early
1980s, contamination of MPTPin heroin was found to cause
parkinsonism in drug abus-ers.17 Since then, MPTP has been used
extensively toinduce neurotoxic experimental PD. The active form
ofMPTP is metabolized in the mitochondria of astrocytesin the SN to
form MPP+ and is then transferred to inhibitcomplex I of the
electron transport chain in neurons,leading to ATP depletion and
accumulation of reactiveoxygen species (ROS).18 Elevated
mitochondrial ROSlevels result in mitochondrial DNA mutations,
proteins/lipids perturbation and can further aect redox
signalingpathways.19 Another widely used neurotoxin, 6-OHDA,induces
pathological events similar to those seen inexperimental PD.20
Numerous studies have shown thatfood components and nutritional
substances can preventor delay the progression of PD by protecting
mitochon-drial function.21 This further supports the role of
mito-chondrial impairment as a major pathological factor
inPD.2224
TREATMENT FOR PATIENTSWITHPARKINSON'S DISEASE
Although PD was rst diagnosed almost two centuriesago, a cure
has yet to be found. Current treatments are
mainly categorized into symptom-relieving drugs andsurgical
treatments. L-dopa, dopamine agonists (prami-pexole, bromocriptine,
pergolide, ropinirole, piribedil,cabergoline, apomorphine, and
lisuride) and MAO-Binhibitors (selegiline and rasagiline) are
examples ofsymptom-relieving drugs, while deep brain
stimulation,implantation of embryonic dopaminergic cells, and
genetherapy have been applied as surgical treatments for
PDpatients. These treatments only aim to improve thequality of life
by attenuating motor or nonmotor symp-toms of PD. As the global
population ages, the need todevelop a disease-modifying drug for PD
is becomingincreasingly urgent.
Existing PD treatments have undesirable eects. Forexample,
L-dopa, a commonly used symptom-relievingdrug for PD, has various
side eects because 9599% of itis metabolized to dopamine in the
body in places otherthan the dopaminergic neurons in the SN.For
this reason,dopa decarboxylase inhibitors (e.g., carbidopa
andbenserazide) and COMT enzyme inhibitors (e.g., tolca-pone and
entacapone) are prescribed in combinationwith L-lopa to enhance its
eect. Discontinuous deliveryof L-dopa has been another limitation
of the treatment.Novel delivery methods of L-dopa seek to overcome
this,such as an intravenous infusion delivery approach and
atransdermal delivery system, both of which have beenapplied in
clinical settings for the past two decades.5,6
POTENTIAL NEUROPROTECTIVE EFFECTSOF NUTRACEUTICALS
Combining the words nutrition and pharmaceutical,the
wordnutraceuticals refers to foods or food productsthat reasonable
clinical evidence suggests may providehealth and medical benets,
including for prevention andtreatment of disease. Such products may
be categorized asdietary supplements, specic diets, herbal
products, orprocessed foods such as cereals, soups, and
beverages.Dietary supplements can be extracts or concentrates
andare found in many forms, including tablets, capsules,liquids,
and powders. Vitamins, minerals, herbs, or iso-lated bioactive
compounds are only a few examples ofdietary ingredients in the
products. Functional foods aredesigned as enriched foods close to
their natural state,providing an alternative to dietary supplements
manufac-tured in liquid or capsule form.
It is generally accepted that neuroprotection pre-vents neurons
from succumbing to damages by dierentinsults. Nutraceuticals can
provide neuroprotection via awide range of proposed mechanisms,
such as scavengingof free radicals and ROS, chelation of
iron,modulation ofcell-signaling pathways, and inhibition of
inammation.25
Neuroprotection can prevent and impede the progressionof PD as
well as the loss of dopaminergic neurons. In the
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following section, the neuroprotective eects of selecteddietary
supplements and functional foods are reviewedand discussed. In
addition, several relevant therapeuticeects are evaluated.
ANTIOXIDANT VITAMIN SUPPLEMENTS(VITAMINS C AND E)
Antioxidant vitamin supplements such as vitamin C,vitamin E (or
tocopherol), and beta-carotene arecommon forms of nutraceuticals.26
A cross-sectionalstudy found that vitamin E supplements are popular
inPD patients, while epidemiological studies have shownthat
consuming foods rich in vitamins C and E are asso-ciated with a
lower risk of developing PD.27 However, itshould be noted that
these studies are not specic toindividual antioxidant nutrients;
rather, it is the foodsrich in these nutrients that are
studied.
Potential neuroprotective eects
An early study has suggested a protective eect of thesetwo
antioxidative vitamins on PD patients.28 In an open-label trial,
high doses of vitamins C and E were adminis-tered to patients in
the early stage of PD. It was found thatpatients who took
antioxidant vitamins had a 2.5- to3-year delay in receiving L-dopa
treatment comparedwith those of Dr. CM Tanner, who did not treat
patientswith vitamins, as reported by Fahn.28 Treatment wasdelayed
from 40months to 72 6.5 months for those PDpatients who started
taking the vitamins before 54 yearsof age, and from 24 months to 63
3.9 months for thosewho started the vitamins after 54 years of age.
Althoughthe placebo eect might be at play here, the delay of
onsetof parkinsonism was remarkably signicant. Anotherreport showed
that vitamin C at 10 mM can reduce neu-rotoxicity elicited by
dopamine metabolism.29
An important double-blind and placebo-controlledclinical study,
the Deprenyl and Tocopherol Antioxi-dative Therapy of Parkinsonism
(DATATOP) by theParkinson Study Group, showed that vitamin E
supple-mentation was not able to delay the need for
introducingL-dopa therapy.30 However, as pointed out in a
commen-tary for this study, the trial did not exclude the
possibilitythat nutritional supplements may delay progression ofPD
by preventing loss of dopaminergic neurons.31 A con-tradicting
report showed that 9.8 IU/day of vitamin Eintake from the diet may
be benecial.32 A meta-analysisproduced similar results, showing
that dietary intake ofvitamin E in moderate amounts may be
neuroprotective.High intake of vitamin C in the form of a
supplement wasnot signicantly protective, with no association
foundbetween vitamin C intake and risk of PD.33
Mechanisms of action
Antioxidant vitamins have a putative role in reducing
theoxidative damage in SN dopaminergic neurons in pro-gressive
disease.34 Vitamin C has been proven in vitro tobe a major
free-radical scavenger in the cytosol, whiletocopherols act as a
major lipid-soluble antioxidant toprevent lipid peroxidation in
membranes. Both vitaminsalso act in a synergistic manner whereby
vitamin C canreduce oxidized vitamin E to restore its
antioxidativefunction.35 Thus, supplemental vitamins can be useful
inprevention or in delaying progression of PD by reducingoxidative
stress.
VITAMIN D
Potential neuroprotective eects
In 2007,Newmark and Newmark36 proposed that vitaminD deciency
had a signicant role in the developmentand progression of PD.
Vitamin D has been found toattenuate 6-OHDA-induced and
MPP+-induced neuro-toxicity, while vitamin D receptor knockout mice
showmotor defect. Moreover, the levels of vitamin-D-bindingprotein
have been proposed as one of the biomarkersfor PD.3739
It has been debated that vitamin D inadequacy in PDpatients is a
result of reduced physical activity and expo-sure to sunlight,
rather than a causal factor in PD pro-gression. However, the
results of a recent longitudinalstudy by Knekt et al. 40 oppose
this view.A large sample ofFinnish adults aged 30 years or older
was selected from1978 to 1980, and blood serum samples were
examined.Occurrences of PD were recorded in a 29-year
follow-upperiod. In 2002, serum levels of vitaminDweremeasured,and
results showed that subjects with higher serumvitamin D levels had
a signicantly lower risk of devel-oping PD.40 These data suggest
that vitamin D levelscould be used as a predictive indicator of PD
risk.
Mechanisms of action
The SN is one of the regions in the brain containing highlevels
of vitamin D receptors and 1a-hydroxylase,40 theenzyme responsible
for the biological activation ofvitamin D. Hence, vitamin D may be
involved in anumber of signaling pathways, and several
mechanismsmay be responsible for the neuroprotective eects
ofvitamin D.
In animal studies, vitamin D was found to upregulateglial cell
line-derived neurotrophic factor levels.37 Glialcell line-derived
neurotrophic factor has been shown tobe antiparkinsonian in animal
and in vitro studies. It can
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promote the outgrowth of dopaminergic axons in striatalneurons
in a region-specic manner and can evenrescue SN neurons from 6-OHDA
toxicity.41 In addi-tion, vitamin D can increase glutathione
levels, regulatecalcium homeostasis, exert anti-apoptotic and
immuno-modulatory eects, reduce nitric oxide synthase, andregulate
dopamine levels.42,43
COENZYME Q10
Potential neuroprotective eects
Coenzyme Q10 (CoQ10 or ubiquinone) is a popular com-mercially
available dietary supplement (Figure 1). It hasbeen recognized as a
neuroprotective agent in the preven-tion and treatment of PD.44
CoQ10 has been demonstratedto prevent the loss of dopaminergic
neurons inMPTP-induced neurotoxicity and parkinsonism.45,46 In
aplacebo-controlled, randomized, double-blind studyinvolving 80
patients with early-stage PD, patients in thetreatment group were
found to have less disability, asevaluated for over 16months using
the Unied ParkinsonDisease Rating Scale. It should be noted that
the eects ofCoQ10 were dose dependent. The group receiving1,200
mg/day, which was the highest dose among the dif-ferent groups,
exhibited a 44% reduction in functionaldecline compared with the
placebo group.47 In anotherstudy, a mild symptomatic benet was
observed using theFarnsworth-Munsell 100 Hue test. The authors
suggestedthat an oral supplement of CoQ10 could achieve a mod-erate
benecial eect, but not a great neuroprotective
eect.48 From these reports, there is no conclusion aboutwhether
the eect of CoQ10 on PD is neuroprotective ormerely symptom
relieving.
Mechanisms of action
CoQ10 is a fat-soluble and vitamin-like quinone foundabundantly
in liver and the brain.49 CoQ10 is particularlyrelevant to
mitochondrial dysfunction because of itsunique electron-accepting
property, which allows it tobridge mitochondrial complex I with
other complexes.CoQ10 plays an important role in maintaining
propertransfer of electrons in the electron transport chain
ofmitochondria and, thus, in the production of ATP as well.As a
result, CoQ10 has a protective eect on dopaminergicneurons in the
SN. In addition, it is a potent antioxidantand can exert its
antioxidant eect by reducing the oxi-dized form of
alpha-tocopherol,50 which is important inthe prevention of lipid
peroxidation.
CREATINE
Potential neuroprotective eects
Creatine has also been investigated for its possible role inthe
treatment and prevention of PD (Figure 1). In a studyusing MPTP in
a PD mouse model, a diet supplementof 1% creatine reduced loss of
dopaminergic neurons inthe SN.51 A placebo-controlled and
randomized pilot trialfor a 2-year period showed that creatine can
improvemood and reduce the dosages required for
dopamine-replacement therapy in the treated group.52
Mechanisms of action
Creatine is considered to be neuroprotective due to itsability
to counter ATP depletion by increasing intracellu-lar
phosphocreatine levels.51 Phosphocreatine is a keyplayer in the
maintenance of ATP levels, which in turnare important in synaptic
activity and skeletal musclefunctions.53,54
UNSATURATED FATTY ACIDS
Potential neuroprotective eects
While unsaturated fatty acids were reported to reduce therisk of
developing PD,55 results from past epidemiologicaland retrospective
studies were inconsistent. To study therelationship, a prospective
study was conducted in twocohorts, the Health Professional
Follow-up Study and theNurses Health Study.56 The authors concluded
that if
Figure 1 Chemical structure of (a) coenzymeQ10 and
(b)creatine.
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saturated fatty acids are replaced by polyunsaturated fattyacids
(PUFAs), the risk of developing PDmay be reduced.In another large
prospective population-based cohortstudy, the Rotterdam Study, the
authors investigated therelationship between dietary unsaturated
fatty acids andthe risk of developing PD.55 In contrast to the
previousstudy, they showed no relationship between the level
ofsaturated fatty acids and the risk of developing PD. Inaddition
to the above studies, the results of a recent inves-tigation on
omega-3 PUFAs suggest a neuroprotectiveeect of omega-3 PUFAs
against dopamine loss and aninhibitory eect against the formation
of dihydroxyphe-nylacetic acid in MPTP-induced parkinsonism in
mice.57
This positive result should encourage future studies onthe
possible mechanism of PUFAs.
Mechanisms of action
PUFAs such as linoleic acid, alpha-linolenic acid,
anddocosahexaenoic acid can be components of cell mem-brane and
precursors of signaling molecules.58 Some ofthese PUFAs cannot be
synthesized in the human bodyand must be obtained from food.
Monounsaturated fattyacids (MUFAs) can also reduce cholesterol and
triacylg-lycerides in plasma.59 Impaired brain function is
stronglyassociated with deciency of MUFAs and PUFAs. Endo-genous
cannabinoids derived fromMUFAs are importantmodulators for
dopaminergic neurons in the basal gan-glia.60 A report has shown
that fatty acid composition inthe brain is highly correlated with
the intake of dietaryfatty acids.61 All these facts justify further
study of therelationship between the intake of unsaturated fatty
acidsand the risk of developing PD.
NATURAL SOURCES OF L-DOPA
Potential neuroprotective eects
To date, natural L-dopa has been found in several
plantsbelonging to Mucuna genus, such as Mucuna pruriens(velvet
bean or mucuna, the seeds of which, in 1937, werefound to contain
L-dopa), Stizolobium deeringianum, andVicia faba (broad bean, in
which L-dopa was identied in1913). M. pruriens (called atmagupta in
India) is aclimbing legume endemic in tropical regions that
includeIndia and Central and SouthAmerica. The plant has
beendocumented in Ayurvedic medicine to treat a neurologi-cal
disorder bearing symptoms similar to those of PD andup to 10% of
the plants volume is L-dopa.62 In recentyears, velvet bean seed
extract has been used for the treat-ment of PD in India.63
Several open-label studies with sample sizes rangingbetween 18
and 60 patients prescribed mucuna seed
powder extract at mean doses of 45 g/day (containingabout 1,500
mg L-dopa). Signicant improvements inparkinsonism were reported and
better tolerabilitywas found compared with standard L-dopa
treatmentalone.6466 In a recent double-blind study involving
eightPD patients, the anti-Parkinsonian eect, tolerability,
andL-dopa pharmacokinetic prole were compared betweenthe mucuna
seed formulation and the commercialL-dopa.67 The results showed
that the eects of 30 g ofM. pruriens formulation were superior to
those of thestandard single doses of 200/50 mg L-dopa/carbidopa.The
bean powder enabled a more rapid onset of action inpatients and had
a slightly longer duration of therapeuticresponse. Moreover, severe
dyskinesia or peripheraldopaminergic adverse events were not found
in themucuna-treated patients. It is suggested that the
mucunaformulation may have greater bioavailability, perhaps as
aresult of synergistic properties of dierent compounds inthe seed
extract.
Mechanisms of action
Most in vitro studies on natural L-dopa sources focus onmucuna.
In 2004, Manyam et al. 68 showed that mucunaseed powder contained
signicant amounts of two neu-roprotective agents, namely nicotine
adenine dinucle-otide (NADH) and CoQ10. Both agents protect
neuronsagainst 6-OHDA toxicity by counteracting the inhibitionof
mitochondrial complex I activity.NADH is also knownto increase
dopamine levels via the upregulation oftyrosine hydrolase.
Mucuna seed powder has also been found to protectneurons against
plasmid DNA and genomic DNAdamage caused by a combination of L-dopa
and divalentcopper ions.69,70 Mucuna seed powder protects
neuronsagainst this type of damage by chelating the divalentcopper
ions present, preventing them from interactingwith L-dopa to
produce the free radicals that will damageDNA molecules.69
POLYPHENOLIC COMPOUNDS
Polyphenolic compounds, or polyphenols, are products ofsecondary
plant metabolism and are widely distributed inthe plant kingdom.
Polyphenolic compounds refer to arange of substances that possess
an aromatic ring bearingmore than one hydroxyl group.More than
8,000 phenolicstructures have been identied. Polyphenols are
generallydivided into hydrolyzable tannins (gallic acid esters
ofglucose and other sugars) and phenylpropanoids, such aslignins,
avonoids, and condensed tannins.
Polyphenols can elicit antioxidant, anti-inammatory,
anticarcinogenic, antimutagenic, and
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antithrombotic eects.71 The neuroprotective eects ofthe major
polyphenolic compounds in green tea, blacktea, coee, curry, and
Scutellaria baicalensis, an herb usedin traditional Chinese
medicine, are reviewed below.
EGCG in green tea
Potential neuroprotective eects. Numerous studiessuggest green
tea may confer health benets due to itspharmacological and
biochemical properties. Epidemio-logical studies have shown an
inverse relationshipbetween tea consumption and the risk of
developing PD.There are several experimental studies showing
neuro-protective eects of green tea on MPTP-induced parkin-sonism
in mouse models and on cell injury inpheochromocytoma PC12 cells
treated by 6-OHDA.72
Many of the benecial eects of green tea are attributedto its
abundant polyphenol content, mainly the avanscalled catechins
(Figure 2).73 There are numerouscatechins found in green tea, the
major ones being(-)-epicatechin (EC), (-)-epicatechin-3-gallate
(ECG),(-)-epigallocatechin (EGC), and
(-)-epigallocatechin-3-gallate (EGCG). EGCG is the most abundant
catechin.74
Levites et al. 75 summarized the biological functions oftea
polyphenols and reported the following benets:free-radical
scavenging and anticarcinogenic, anti-inammatory, and
antiangiogenic eects.
Mechanisms of action. Dierent mechanisms have beenproposed for
the neuroprotective activity of EGCG in PD.The study conducted by
Levites et al. 75 was the rst todemonstrate the neuroprotective
activity of both greentea extract (0.5 and 1 mg/kg) and EGCG (2 and
10 mg/kg) on MPTP-induced parkinsonism in animal models. Itis
possible that the neuroprotective eects are mediatedby
iron-chelating activities and free-radical-scavengingactivities
possessed by the catechol group. Since green teacatechins can pass
through the blood-brain barrier, theycan act as both ROS scavengers
and iron chelators to clearthe redox active ferrous iron deposited
in the SN, reduc-ing the iron-induced oxidative stress that can
lead to neu-ronal death.
The putative neuroprotective eects of green tea cat-echins also
may be mediated via other mechanisms.Mandel et al. 73 and Levites
et al. 76 summarized theneuroprotective mechanisms of green tea
catechins asregulation of protein kinase C activity and inductionof
endogenous antioxidant defense systems. A recentexperimental study
using the 6-OHDA rat model ofPD also suggests that green tea
catechins protect theSN dopaminergic neurons through modulation of
theROS-NO pathway.77 It appears there is considerable evi-dence to
support the putative neuroprotective eects ofgreen tea.
Nonetheless, much of the evidence was derived
from experimental and animal studies, while evidencefrom large
prospective studies or case-control studies spe-cic to green tea
catechins rather than to general teaconsumption is limited. In
contrast to other reportsshowing benecial eects of green tea, the
prospectivecohort study of the Singapore Chinese Health Study78
showed no relationship between green tea consumptionand the risk
of developing PD if caeine intake wasexcluded. Therefore, more
studies of green tea consump-tion in humans and the risk of
developing PD are requiredto verify the possible protective eect of
green tea.
Curcuminoids in curry
Potential neuroprotective eects. Curcumin (1,7-bis[4-hydroxy
3-methoxy phenyl]-1,6-heptadiene-3,5-dione) isa polyphenolic
avonoid that constitutes approximately4% of turmeric, which has a
long history of use in tradi-
Figure 2 Chemical structure of polyphenolic com-pounds (a) EGCG,
(b) curcuminoids, and (c) baicalein.
Nutrition Reviews Vol. 70(7):373386 379
-
tional Asian diets and herbal medicines (Figure 2). Cur-cumin is
the principal curcuminoid in turmeric. Theother two curcuminoids
are desmethoxycurcumin andbisdesmethoxycurcumin. Curcuminoids,
rather than cur-cumin alone, are commercially available and are
generallyused in experimental studies. The bioactive eects of
cur-cuminoids have often been attributed to curcumin, as
thecurcumin content of curcuminoids reaches up to 80%.
Mechanisms of action. Like other polyphenolic com-pounds such as
caeic acid, EGCG, and resveratrol, cur-cumin is well known for its
powerful antioxidantproperties. Jagatha et al.79 reported that
curcumin treat-ment of mice and of dopaminergic neurons in cell
cul-tures attenuated oxidative stress by restoring
glutathionelevels, thereby protecting neurons against protein
oxida-tion and preserving mitochondrial complex I activity.The
reduction of 6-OHDA-induced neurotoxicity inMES 23.5 cells and in a
rat model of PD has been attrib-uted to the antioxidant properties
of curcumin.80 In addi-tion, curcumins direct modulation of
6-OHDA-inducednuclear factor-kappa B (NF-kB) translocation
confersneuroprotective eects in dopaminergic neuronal cells ofthe
MES 23.5 cell line.81
Curcumin has also been found to exhibit anti-inammatory
properties. In primary cultures of rat mes-encephalic
neuronal/glial cells, curcumin inhibitedlipopolysaccharide
(LPS)-induced morphologicalchanges of microglia and dramatically
reduced LPS-induced production of many proinammatory factorsand
their gene expressions. LPS-induced activation oftranscription
factors, such as NF-kB and activatorprotein-1, were also attenuated
by curcumin treatment.82
In addition, curcumin has been found to preventMPTP/MPP+-induced
neurotoxicity in C57BL/6N mice,SH-SY5Y cells, and PC12 cells by
targeting the JNK, theBcl-2-mitochondria, and the ROS-iNOS
(inducible nitricoxide synthase) pathways.83,84 Systemic
administrationof curcumin (80 mg/kg i.p.) and its metabolite
tetrahy-drocurcumin (60 mg/kg i.p.) signicantly
reversedMPTP-induced depletion of DA and DOPAC (3,4-dihydroxy
phenyl acetic acid) in mice. The authors con-cluded that the
reversion may be, in part, due to theinhibition of MAO-B activity
by these compounds.85
Furthermore, both overexpression and abnormalaccumulation of
aggregated alpha-synuclein (AS) havebeen found to be closely linked
to PD. Recent studiesrevealed that curcumin could inhibit
aggregation of AS incell-free conditions and in a cellular model of
A53T-ASoverexpression.86,87
Ortiz-Ortiz et al.,88 however, called for re-evaluationof the
potential of curcumin as a therapeutic agent inneurodegenerative
diseases. In contrast to ndingsreported previously by
others,Ortiz-Ortiz et al. 89 surpris-
ingly found that exposure of N27 mesencephalic cells to10 nM
curcumin synergistically enhanced paraquat-mediated apoptosis. A
very recent study from the samegroup found that exposure of rat
mesencephalic cells to10 nM curcumin induced the expression of
LRRK2 inmRNA and protein levels, although there was no eect onother
PD-related genes like AS and parkin. Overexpres-sion of LRRK2 is
strongly associated with the pathologi-cal inclusions found in PD.
Taken together, the ndingsfor curcumin remain controversial and
await furtherexperimental and clinical studies.
Baicalein
Potential neuroprotective eects. Baicalein is a avonoidextracted
from the root of Scutellaria baicalensis, a tradi-tional Chinese
herb commonly known as Huang Qin.Baicalein has been shown to be a
potent antioxidant in ratprimary neurons (Figure 2).90 Another
study in rats alsoshowed anti-inammatory properties of baicalein
inexperimental traumatic brain injury.91 Baicalein wasfound to be
neuroprotective in several experimentalmodels of PD, including
MPTP-induced neurotoxicityand 6-OHDA-induced neurotoxicity.92,93 It
has also beenshown to inhibit brillization of AS.94 In a recent
study,baicalein attenuated depolarization of mitochondria
andproteasome inhibition in PC12 cells induced by the E46Kmutation,
an AS mutation linked to familial parkin-sonism.95 The mechanisms
underlying the neuroprotec-tive eects of baicalein, however, remain
unclear.
STILBENES
Stilbenes are a class of antioxidants sharing the samechemical
skeleton of a diarylethene, which is a hydrocar-bon consisting of a
trans/cis ethene double bond substi-tuted with a phenyl group on
both carbon atoms of thedouble bond. The name stilbene was derived
from theGreek word stilbos, which means shining. Many stil-benes
and their derivates (stilbenoids) are naturallypresent in plants
(dietary fruits or herbs).
Resveratrol
Potential neuroprotective eects. The most widelyinvestigated
stilbene is resveratrol (3, 4, 5-trans-trihydroxystilbene, RES,
Figure 3), a phytoalexin found inplants such as grapes, peanuts,
berries, and pines.96 RES issynthesized in these plants to
counteract various environ-mental injuries, such as UV irradiation
and fungal infec-tion. RES is reported to be one of the active
agents inItadori tea, which has been used as a traditional
medicinein China and Japan, mainly for treating heart disease
andstroke.97 Epidemiological studies reporting the inverse
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-
association between moderate consumption of red wineand the
incidence of coronary heart disease have stimu-lated investigations
on the cardioprotective activity ofRES.98 In recent years, numerous
studies have shown thatRES can protect dopaminergic neurons against
toxicityinduced by LPS, DA, or MPP+.99101 The neuroprotectiveeects
of RES have also been reported in 6-OHDA-lesioned rats and in mouse
models of MPTP-inducedneuronal loss.102,103
Mechanisms of action. The underlying mechanisms
ofneuroprotection by RES include the inhibition ofNADPH oxidase and
the suppression of proinamma-tory genes such as interleukin 1-a and
tumor necrosisfactor-a triggered by LPS.99,104 Pretreatment with
RESreduced apoptosis in PC12 cells by modulating mRNAlevels and
protein expression levels of BAX and Bcl-2 invitro.100 RES may
stimulate SIRT1 in 6-OHDA-triggeredSK-N-BE cells, as indicated by
the loss of protection in thepresence of the SIRT1 inhibitor
sirtinol, a loss that alsooccurred when SIRT1 expression was
downregulated bysiRNA approach.105107 In addition, RES exhibits
neuro-protective eects on MPTP-induced motor
coordinationimpairment, hydroxyl radical overloading, and
neuronalloss through free-radical-scavenging activity.102
Oxyresveratrol
Potential neuroprotective eect. Recent studies havefound that
RES may not be the most eective neuro-protective agent.
Investigations on the dierentialbioactivities of RES and
oxyresveratrol (OXY) (2, 3, 4,5-trans-trihydroxystilbene, Figure 3)
have shownOXY to
be a more eective neuroprotective agent. OXY is foundin the
heartwood or fruit of Artocarpus heterophyllus,Artocarpus lakoocha,
Artocarpus gomezianus, and Arto-carpus dadah, in the wood or fruit
of mulberry trees(Morus australis, Morus alba L.), in the fruit of
Melaleucaleucadendron, in rhizomes of Smilacis chinae, and in
theEgyptian herb Schoenocaulon ocinale.
Mechanisms of action. In vivo and in vitro studies haveshown
anti-inammatory eects of OXY, particularlyOXY isolated from
Artocarpus heterophyllus, Artocarpusdadah, or mulberry wood.108,109
OXY can also reduce theproduction of beta-amyloid by inhibiting
b-secretase 1.110OXY has been demonstrated to protect against
6-OHDA-induced toxicity in SH-SY5Y cells by reducing the releaseof
lactate dehydrogenase and caspase-3 specic activity.111
Analysis by high-performance liquid chromatographyshowed that
OXY readily penetrates into neurons,thereby suppressing the level
of intracellular ROS by itspotent free-radical-scavenging activity.
OXY was alsofound to upregulate SIRT1 levels, indicating that the
neu-roprotective properties of SIRT1may be attributable to
itsactivation.111
PHYTOESTROGENS
It has been known that the incidence of PD is lower inwomen than
in men (using age controls), indicating aprotective eect of
estrogen or its derivatives.112 The inci-dence of PD is also lower
in premenopausal womenthan in postmenopausal women.113 The
neuroprotectiveeects of estrogen have been shown in many
studies,including upregulation of Bcl-2 and brain-derived
neu-rotrophic factor.114 However, numerous side eects dis-courage
women from receiving hormone replacementtherapy. Phytoestrogens,
obtained through either the dietor supplements, provide an
alternative to traditionalhormone replacement therapy without some
of thereported side eects; this will be discussed in the follow-ing
section.
Phytoestrogens are a group of substances that arefound naturally
in plants and possess a common chemicalstructure similar to that of
estradiol. Major food sourcesof phytoestrogens include soy
products, nuts, and grains.Two types of phytoestrogens are
discussed below.
Ginsenoside Rg1
Potential neuroprotective eects. Ginsenosides are a classof
molecules extracted from several species of ginseng.Ginseng has a
long history in traditional Chinese medi-cine, Indian herbal
medicine, and the medicine of otherAsian cultures, and it is well
known for its antiagingeects. Rg1 is a ginsenoside isolated from
the root of
Figure 3 Chemical structure of (a) trans-resveratrol and(b)
trans-oxyresveratrol.
Nutrition Reviews Vol. 70(7):373386 381
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Panax ginseng. It is one of the relatively well-studied
gin-senosides (Figure 4). In vivo, Rg1 can attenuate
6-OHDAneurotoxicity, MPTP-induced neurotoxicity, and oxida-tive
stress.112,115 It can also suppress tumor proliferation.116
In vitro studies have shown that Rg1 can attenuate roten-one
toxicity.117
Mechanisms of action. Ginsenoside Rg1 has been foundto regulate
several signaling pathways, which may explainits neuroprotective
eects. The signaling pathways modu-lated by ginsenoside Rg1 include
PI3K/Akt, ERK, JNK,ROS-NFkB, IGF-1 receptor signaling pathways,
andestrogen receptor pathway.115,118120
In 2005,Chen et al. 115 tested the eects of Rg1
againstMPTP-induced neurotoxicity in mice. Results showedthat Rg1
was able to reduce neuronal loss caused byMPTP toxicity through two
possible mechanisms. First,Rg1 prevented the reduction of
glutathione. Second, Rg1attenuated phosphorylation of c-Jun, as JNK
signalingcan be proapoptotic.115,121 A third mechanism was
pro-posed by Wang et al.122 in 2009. By iron staining, theauthors
showed, in a mouse model of MPTP toxicity, thatelevated iron levels
in the SN were linked to neuronaldeath. Rg1 prevented this
elevation of iron levels by regu-lating the expression of iron
transport proteins such asferroportin 1 and divalent metal
transport 1.122
Rg1 is also benecial to the maintenance of mito-chondrial
functions. In the presence of rotenone, Rg1restored depleted
mitochondrial membrane potential.117
Antiapoptotic eects included inhibition of cytochrome crelease
and activation of the PI3K/Akt cell survivalpathway, resulting in
enhanced inhibition of Bad proteinexpression.117 Upon blocking the
glucocorticoid receptorwith an antagonist, these eects were
blocked, indicatingthat Rg1 mediates its eects through the
glucocorticoidreceptor.117
Genistein
Potential neuroprotective eects. Soy and peanuts are richdietary
sources of the phytoestrogen genistein, which hasbeen found to be
the primary circulating soy isoavone(Figure 4).123 In fact, dietary
soy is widely used as an alter-native to traditional hormonal
replacement therapy. In2007, a study was conducted byAzadbakht et
al. 124 to ndthe eects of dietary soy on postmenopausal women
withmetabolic syndrome. Compared with normal subjects,the
postmenopausal women had reduced plasma levels ofmalondialdehyde,
an oxidative stress marker. Numerousstudies in rats have shown that
treatment with genisteinisolated from plant sources results in
similar antioxida-tive eects and antiapoptotic eects.
Mechanisms of action. Many studies have shown thatgenistein
binds to estrogen receptors in the centralnervous system. The
estrogen receptor b has been foundto have a particularly high
binding anity for genistein.125
Upon binding to the estrogen receptor, the genistein-receptor
complex acts as a transcriptional activator toupregulate
antioxidative and antiapoptotic genes.123,126
The antioxidative eects of genistein have beenattributed to its
ability to increase the levels of malondi-aldehyde, superoxide
dismutase, and monoamine oxi-dase.124,127 On the other hand,Kaul et
al. 128 concluded thatgenistein specically attenuated the
generation of ROS,but not oxidative stress.128 They conducted an
experimenttesting the eect of genistein on
hydrogen-peroxide-induced cell death in rat mesencephalic
dopaminergicneurons known as N27 cells. While no
antioxidativemechanism was suggested, the authors showed
thatgenistein acted as a tyrosine kinase inhibitor,
therebyattenuating the activation of protein kinase C gamma andits
downstream proapoptotic eects.128
In addition, it has been proposed that genistein maybe able to
regulate activity of dopaminergic neuronsbecause estradiol has been
shown to play a role in regu-lation of the neurotransmitter in
animal studies.125 Arecent study testing the eects of genistein
treatmentprior to intrastriatal 6-OHDA lesions in rats is in line
withthis hypothesis. It was found that genistein pretreatment
Figure 4 Chemical structure of (a) ginsenoside Rg1 and(b)
genistein.
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attenuated rotational behavior in rats, a symptom
ofparkinsonism.126
POTENTIAL APPLICATIONS OF NUTRACEUTICALS INCURRENT PD
THERAPY
The potential benets of nutraceuticals in PDmay extendfrom
prevention to the delay of disease progression. Fur-thermore,
dietary supplements or functional foods mayreduce the side eects of
current treatments or enhancethe bioavailability of L-dopa.
B vitamins and hyperhomocysteinemia
Numerous studies have demonstrated that treatment withL-dopa in
PD patients induces high levels of homocys-teine (HHcy). Studies
show that HHcy is a substantial riskfactor for cardiovascular,
cerebrovascular, and peripheralvascular diseases as well as
cognitive impairment anddementia.129 L-dopa administered to PD
patients ismetabolized to 3-O-methyl-dopa via methlyation byCOMT in
peripheral tissues. S-adenosyl-methionine(SAM) provides the methyl
group in the reaction and isconverted to S-adenosyl-homocysteine
(SAH) afterdonation of the methyl group to L-dopa.
Subsequentmetabolic reactions metabolize SAH to HHcy, resultingin
increased levels of HHcy in plasma.130 It is well recog-nized that
high levels of HHcy can be caused by decien-cies in any one of the
three important B vitamins, namely,folate, vitamin B12, and vitamin
B6, 129 because HHcy canbe catabolized to cysteine by a chain
reaction in whichvitamin B6 acts as a cofactor, while methionine
synthase,an enzyme using vitamin B12 as a cofactor, and
5-methyl-tetrahydrofolate can also metabolize HHcy to
methion-ine.130 Reports have shown that PD patients treated
withL-dopa exhibit higher HHcy levels in plasma, but a sig-nicant
reduction in HHcy levels was observed in PDpatients supplemented
with folate, vitamin B12, andvitamin B6. Therefore, supplementation
with these vita-mins is important for managing the elevated HHcy
levelsin PD patients.129,131
Vitamin C, hydrosoluble ber, and pharmacokinetics
Although ndings about the ecacy of the neuroprotec-tive eects of
vitamin C were inconclusive, vitamin Cmayimprove the ecacy of
L-dopa. In a pharmacokineticstudy, vitamin C was found to enhance
absorption ofL-dopa in elderly patients with PD.132 Another
studyusing water-soluble ber of Plantago ovata husk showedthat
treatment of the plant with L-dopa/carbidopabenets PD patients by
relieving constipation andimproving the L-dopa prole.133 These
studies suggest
that functional foods can help patients via augmentationwith
drug therapy.
CONCLUSION
The relationship between diet and disease prevention isnot a new
concept. In fact, the basic theory in Chineseherbal medicine,
medicine and diet share the sameorigins, emphasizes that scientic
diet strategy may playan undeniable role in human health. One after
another,studies have shown the importance of a nutritious dietand
active lifestyle as a healthy aging strategy in the pre-vention of
most aging-related diseases, such as cancer,cardiovascular disease,
and neurodegenerative diseases.In fact, many populations worldwide
have embraced thisconcept for generations and have incorporated
variouskinds of nutraceuticals in their diet. Not only should
thisconcept be encouraged as part of daily living to
preventdisease, it should also be promoted and applied in a
clini-cal setting.
Nutraceuticals and diet strategies do more than justimprove the
quality of life for patients.As discussed,whenapplied in
combination with L-dopa drug therapy,B-complex vitamins and vitamin
C have positive eects,including reduced side eects and enhanced
absorptionof L-dopa.These nutraceuticals enhance the eect of
con-temporary drug therapy and may allow for an attenuateddrug
dosage, further reducing any dose-dependent sideeects. There is
much potential in the positive synergisticeects between
nutraceuticals and clinical drug therapy.Hence, instead of
identifying the neuroprotective eectsof nutraceuticals alone,
future research should focus onthe eects of nutraceuticals in
combination with drugtherapy. Furthermore, enhanced drug therapy
may bedeveloped through design and application of co-drugslinking
nutraceuticals and therapeutic drugs, e.g., bylinking stilbene
compounds to L-dopa or even by linkingcurcuminoids to L-dopa. This
strategy of linking nutra-ceuticals to drugs may contribute to new
drug designs aswell as to more well-designed experimental studies
andclinical trials.
Nutraceuticals, though attractive and benecial, arestill not the
cure for PD. Experimental evidence is toolimited to enable the
development of eective drugs fromnutraceuticals. Well-designed and
placebo-controlledhuman intervention trials are undoubtedly
required toconrm experimental ndings. Many of the nutraceuti-cals
discussed in this review have been shown to be notonly preventative
but also therapeutic for PD. Nonethe-less, there are still many
unknowns, especially with regardto the pharmacokinetics and
pharmacodynamics of thesenutraceuticals, the eective intake dosage,
and the exacttherapeutic target, all of which hinders their usage
in a
Nutrition Reviews Vol. 70(7):373386 383
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clinical setting. High-quality research is needed topromote the
entry of more nutraceuticals into therapeu-tic usage.
Acknowledgments
Nutraceutical research in PD in this laboratory is sup-ported by
HKU Seed Funding for Applied Research(200907162006) and HKU
Strategic Research Theme onDrug Discovery.
Declaration of interest. The authors have no relevantinterests
to declare.
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