Parkinson's Nutraceuticals

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Nutraceuticals and their preventive or potential therapeutic value 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 the world, after Alzheimer's disease. It is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and other parts of the brain, leading to motor impairment, cognitive impairment, and dementia. Current treatment methods, such as L-dopa therapy, are focused only on relieving symptoms and 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 research has revealed a number of major risk factors, including oxidative stress and mitochondrial dysfunction. Moreover, numerous nutraceuticals have been found to target and attenuate these risk factors, thereby preventing or delaying the progression 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 the prevention or delay of PD as well as the mechanisms of action of nutraceuticals and their potential applications as therapeutic agents, either alone or in combination with current treatment methods. © 2012 International Life Sciences Institute INTRODUCTION Parkinson’s disease (PD) is regarded as the second most prevalent aging-related neurodegenerative disorder after Alzheimer’s disease (AD), affecting approximately 0.017% of people between the ages of 50 and 59 years, with a median onset age of around 60 years. Aging is undoubtedly a major risk factor of PD, as the incidence of PD jumps to approximately 0.093% in people between the ages of 70 and 79 years. In people over 70 years of age, the number of men diagnosed with PD is about 1.5 times higher than that of women. 1 Environmental toxins and exposure to pesticides have 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 disulfide, and cyanide, 2 while examples of pesti- cides include paraquat, organophosphates, and rotenone. 3 MPTP exposure has been found to induce both loss of dopaminergic neurons and clinical parkinsonism. Simi- larly, rotenone and paraquat, when applied to experi- mental animals, have been found to induce loss of dopaminergic neurons and typical parkinsonism. 4 As potential etiological factors of PD, environmental Affiliations: J Chao is with the Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of 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 of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. M Wang is with the School of Biological Sciences, Faculty of Science, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. RC-C Chang is with the Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China, and the Research Centre of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong 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 of Medicine, 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 Lead Article doi:10.1111/j.1753-4887.2012.00484.x Nutrition Reviews® Vol. 70(7):373–386 373

description

Treatment of symptoms of Parkinsons with some nutraceuticals.This article discusses the use of researched nutraceuticals on the symptoms of Parkinsons

Transcript of Parkinson's Nutraceuticals

  • 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.

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  • 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.

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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

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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.

    REFERENCES

    1. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies ofParkinsons disease. Mov Disord. 2003;18:1931.

    2. Frigerio R, Sanft KR, Grossardt BR, et al. Chemical exposures and Parkinsonsdisease: a population-based case-control study. Mov Disord. 2006;21:16881692.

    3. Ascherio A, Chen H, Weisskopf MG, et al. Pesticide exposure and risk for Parkin-sons disease. Ann Neurol. 2006;60:197203.

    4. Cicchetti F, Lapointe N, Roberge-Tremblay A, et al. Systemic exposure toparaquat and maneb models early Parkinsons disease in young adult rats.Neurobiol Dis. 2005;20:360371.

    5. Fahn S. Parkinsons disease: 10 years of progress, 19972007. Mov Disord.2010;25(Suppl 1):S2S14.

    6. Schapira AH, Agid Y, Barone P, et al. Perspectives on recent advances in theunderstanding and treatment of Parkinsons disease. Eur J Neurol. 2009;16:10901099.

    7. Forloni G, Terreni L, Bertani I, et al. Protein misfolding in Alzheimers and Par-kinsons disease: genetics and molecular mechanisms. Neurobiol Aging.2002;23:957976.

    8. Martinez-VicenteM, Cuervo AM. Autophagy and neurodegeneration: when thecleaning crew goes on strike. Lancet Neurol. 2007;6:352361.

    9. Rubinsztein DC. The roles of intracellular protein-degradation pathways in neu-rodegeneration. Nature. 2006;443:780786.

    10. Halliwell B. Oxidative stress and neurodegeneration: where are we now?J Neurochem. 2006;97:16341658.

    11. Youdim MB, Riederer P. Understanding Parkinsons disease. Sci Am. 1997;276:5259.

    12. Castellani RJ, Perry G, Siedlak SL, et al. Hydroxynonenal adducts indicate a rolefor lipid peroxidation in neocortical and brainstem Lewy bodies in humans.Neurosci Lett. 2002;319:2528.

    13. Sudha K, Rao AV, Rao S, et al. Free radical toxicity and antioxidants in Parkin-sons disease. Neurol India. 2003;51:6062.

    14. Perier C, Bove J, Wu DC, et al. Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinsonsdisease. Proc Natl Acad Sci U S A. 2007;104:81618166.

    15. Beal MF. Mitochondria, oxidative damage, and inammation in Parkinsonsdisease. Ann N Y Acad Sci. 2003;91:120131.

    16. Hartmann A, Hunot S, Michel PP, et al. Caspase-3: a vulnerability factor andnal eector in apoptotic death of dopaminergic neurons in Parkinsonsdisease. Proc Natl Acad Sci U S A. 2000;97:28752880.

    17. Langston JW, Ballard P, Tetrud JW, et al. Chronic parkinsonism in humans dueto a product of meperidine-analog synthesis. Science. 1983;219:979980.

    18. Reichmann H, Janetzky B. Mitochondrial dysfunction a pathogenetic factor inParkinsons disease. J Neurol. 2000;247(Suppl 2):II63II68.

    19. Lambert AJ, Brand MD. Reactive oxygen species production by mitochondria.Methods Mol Biol. 2009;554:165181.

    20. Emborg ME. Evaluation of animal models of Parkinsons disease for neuropro-tective strategies. J Neurosci Methods. 2004;139:121143.

    21. Liu J, Ames BN. Reducing mitochondrial decay with mitochondrial nutrients todelay and treat cognitive dysfunction, Alzheimers disease, and Parkinsonsdisease. Nutr Neurosci. 2005;8:6789.

    22. Khrapko K, Vijg J. Mitochondrial DNAmutations and aging: devils in the details?Trends Genet. 2009;25:9198.

    23. Trifunovic A, Larsson NG. Mitochondrial dysfunction as a cause of ageing.J Intern Med. 2008;263:167178.

    24. Fato R, Bergamini C, Leoni S, et al. Generation of reactive oxygen species bymitochondrial complex I: implications in neurodegeneration. Neurochem Res.2008;33:24872501.

    25. Chaturvedi RK, Shukla S, Seth K, et al. Neuroprotective and neurorescue eectof black tea extract in 6-hydroxydopamine-lesioned rat model of Parkinsonsdisease. Neurobiol Dis. 2006;22:421434.

    26. Maxwell SRJ. Antioxidant vitamin supplements: update of their potential ben-ets and possible risks. Drug Saf. 1999;21:253266.

    27. Anderson C, Checkoway H, Franklin GM, et al. Dietary factors in Parkinsonsdisease: the role of food groups and specic foods. Mov Disord. 1999;14:2127.

    28. Fahn S. An open trial of high-dosage antioxidants in early Parkinsons disease.Am J Clin Nutr. 1991;53:S380S382.

    29. Martin A, Youdim K, Szprengiel A, et al. Roles of vitamins E and C on neurode-generative diseases and cognitive performance. Nutr Rev. 2002;60:308326.

    30. The Parkinson Study Group. Eects of tocopherol and deprenyl on the pro-gression of disability in early Parkinsons disease. N Engl J Med. 1993;328:176183.

    31. Olanow CW. Dietary vitamin E and Parkinsons disease: something to chew on.Lancet Neurol. 2003;2:74.

    32. Zhang SM, Hernan MA, Chen H, et al. Intakes of vitamins E and C, carotenoids,vitamin supplements, and PD risk. Neurology. 2002;59:11611169.

    33. Etminan M, Gill SS, Samii A. Intake of vitamin E, vitamin C, and carotenoids andthe risk of Parkinsons disease: a meta-analysis. Lancet Neurol. 2005;4:362365.

    34. Scheider WL, Hershey LA, Vena JE, et al. Dietary antioxidants and other dietaryfactors in the etiology of Parkinsons disease. Mov Disord. 1997;12:190196.

    35. Verhagen H, Buijsse B, Jansen E, et al. The state of antioxidant aairs. NutrToday. 2006;41:244250.

    36. Newmark HL, Newmark J. Vitamin D and Parkinsons disease a hypothesis.Mov Disord. 2007;22:461468.

    37. Wang JY, Wu JN, Cherng TL, et al. Vitamin D attenuates 6-hydroxydopamine-induced neurotoxicity 3 in rats. Brain Res. 2001;904:6775.

    38. Shinpo K, Kikuchi S, Sasaki H, et al. Eect of 1,25-dihydroxyvitamin D3 on cul-tured mesencephalic dopaminergic neurons to the combined toxicity causedby L-buthionine sulfoximine and 1-methyl-4-phenylpyridine. J Neurosci Res.2000;62:374382.

    39. Zhang J, Sokal I, Peskind ER, et al. CSF multianalyte prole distinguishes Alz-heimer and Parkinson diseases. Clin Chem. 2008;129:526529.

    40. Knekt P, Kilkkinen A, Rissanen H, et al. Serum vitamin D and the risk of Parkin-son disease. Arch Neurol. 2010;67:808811.

    41. Kirik D, Georgievska B, Rosenblad C, et al. Delayed infusion of GDNF promotesrecovery of motor function in the partial lesion model of Parkinsons disease.Eur J Neurosci. 2001;13:15891599.

    42. Garcion E, Wion-Barbot N, Montero-Menei CN, et al. New clues about vitamin Dfunctions in the nervous system. Trends Endocrinol Metab. 2002;13:100105.

    43. Evatt ML, Delong MR, Khazai N, et al. Prevalence of vitamin D insuciency inpatients with Parkinson disease and Alzheimer disease. Arch Neurol. 2008;65:13481352.

    44. Shults CW. Therapeutic role of coenzyme Q(10) in Parkinsons disease. Pharma-col Ther. 2005;107:120130.

    45. Beal MF, Matthews RT, Tieleman A, et al. Coenzyme Q10 attenuates the1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP) induced loss of striataldopamine and dopaminergic axons in agedmice. Brain Res. 1998;783:109114.

    46. Cleren C, Yang L, Lorenzo B, et al. Therapeutic eects of coenzyme Q10 (CoQ10)and reduced CoQ10 in the MPTP model of Parkinsonism. J Neurochem. 2008;104:16131621.

    47. Shults CW, Oakes D, Kieburtz K, et al. Eects of coenzyme Q10 in early Parkin-son disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59:15411550.

    48. Muller T, Buttner T, Gholipour AF, et al. Coenzyme Q10 supplementation pro-vides mild symptomatic benet in patients with Parkinsons disease. NeurosciLett. 2003;341:201204.

    49. Bonakdar RA, Guarneri E. Coenzyme Q10. Am Fam Physician. 2005;72:10651070.

    50. Shults CW, Haas RH, Beal MF. A possible role of coenzyme Q10 in the etiologyand treatment of Parkinsons disease. Biofactors. 1999;9:267272.

    51. Matthews RT, Ferrante RJ, Klivenyi P, et al. Creatine and cyclocreatine attenuateMPTP neurotoxicity. Exp Neurol. 1999;157:142149.

    52. Bender A, Koch W, Elstner M, et al. Creatine supplementation in Parkinsondisease: a placebo-controlled randomized pilot trial. Neurology. 2006;67:12621264.

    53. Beal MF. Therapeutic approaches to mitochondrial dysfunction in Parkinsonsdisease. Parkinsonism Relat Disord. 2009;15(Suppl 3):S189S194.

    54. Valastro B, Dekundy A, Danysz W, et al. Oral creatine supplementation attenu-ates L-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned rats. BehavBrain Res. 2009;197:9096.

    55. de Lau LM, Bornebroek M, Witteman JC, et al. Dietary fatty acids and the risk ofParkinson disease: the Rotterdam Study. Neurology. 2005;64:20402045.

    56. Chen H, Zhang SM, Hernan MA, et al. Dietary intakes of fat and risk of Parkin-sons disease. Am J Epidemiol. 2003;157:10071014.

    Nutrition Reviews Vol. 70(7):373386384

  • 57. Bousquet M, Saint-Pierre M, Julien C, et al. Benecial eects of dietary omega-3polyunsaturated fatty acid on toxin-induced neuronal degeneration in ananimal model of Parkinsons disease. FASEB J. 2008;22:12131225.

    58. Fernstrom JD. Can nutrient supplements modify brain function? Am J Clin Nutr.2000;71:S1669S1675.

    59. Kris-Etherton PM, Pearson TA, Wan Y, et al. High-monounsaturated fatty aciddiets lower both plasma cholesterol and triacylglycerol concentrations. Am JClin Nutr. 1999;70:10091015.

    60. Garcia-Arencibia M, Garcia C, Fernandez-Ruiz J. Cannabinoids and Parkinsonsdisease. CNS Neurol Disord Drug Targets. 2009;8:432439.

    61. Julien C, Berthiaume L, Hadj-Tahar A, et al. Postmortem brain fatty acid proleof levodopa-treated Parkinson disease patients and parkinsonian monkeys.Neurochem Int. 2006;48:404414.

    62. Manyam BV. Paralysis agitans and levodopa in Ayurveda: ancient Indianmedical treatise. Mov Disord. 1990;5:4748.

    63. Manyam BV, Sanchez-Ramos JR. Traditional and complementary therapies inParkinsons disease. Adv Neurol. 1999;80:565574.

    64. Vaidya AB, Rajagopalan TG, Mankodi NA, et al. Treatment of Parkinsons diseasewith the cowhage plant Mucuna pruriens Bak. Neurol India. 1978;26:171176.

    65. Nagashayana N, Sankarankutty P, Nampoothiri MR, et al. Association of L-dopawith recovery following Ayurveda medication in Parkinsons disease. J NeurolSci. 2000;176:124127.

    66. HP200 in Parkinsons Disease Study Group. An alternative medicine treatmentfor Parkinsons disease: results of a multicenter clinical trial. J Altern Comple-ment Med. 1995;1:249255.

    67. Katzenschlager R, Evans A, Manson A, et al. Mucuna pruriens in Parkinsonsdisease: a double blind clinical and pharmacological study. J Neurol NeurosurgPsychiatry. 2004;75:16721677.

    68. Manyam BV, Dhanasekaran M, Hare TA. Neuroprotective eects of the antipar-kinson drug Mucuna pruriens. Phytother Res. 2004;18:706712.

    69. Tharakan B, Dhanasekaran M, Mize-Berge J, et al. Anti-Parkinson botanicalMucuna pruriens prevents levodopa induced plasmid and genomic DNAdamage. Phytother Res. 2007;21:11241126.

    70. Spencer JP, Jenner A, Aruoma OI, et al. Intense oxidative DNA damage pro-moted by L-dopa and its metabolites. Implications for neurodegenerativedisease. FEBS Lett. 1994;353:246250.

    71. Urquiaga I, Leighton F. Plant polyphenol antioxidants and oxidative stress. BiolRes. 2000;33:5564.

    72. Pan T, Jankovic J, Le W. Potential therapeutic properties of green tea polyphe-nols in Parkinsons disease. Drugs Aging. 2003;20:711721.

    73. Mandel S, Weinreb O, Amit T, et al. Cell signaling pathways in the neuroprotec-tive actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: impli-cations for neurodegenerative diseases. J Neurochem. 2004;88:15551569.

    74. Weinreb O, Mandel S, Amit T, Youdim MB. Neurological mechanisms of greentea polyphenols in Alzheimers and Parkinsons diseases. J Nutr Biochem.2004;15:506516.

    75. Levites Y, Weinreb O, Maor G, et al. Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induceddopaminergic neurodegeneration. J Neurochem. 2001;78:10731082.

    76. Mandel S, Weinreb O, Reznichenko L, et al. Green tea catechins as brain-permeable, non toxic iron chelators to iron out iron from the brain. J NeuralTransm Suppl. 2006;71:249257.

    77. Guo S, Yan J, Yang T, et al. Protective eects of green tea polyphenols in the6-OHDA rat model of Parkinsons disease through inhibition of ROS-NOpathway. Biol Psychiatry. 2007;62:13531362.

    78. Tan LC, Koh WP, Yuan JM, et al. Dierential eects of black versus green tea onrisk of Parkinsons disease in the Singapore Chinese Health Study. Am J Epide-miol. 2008;167:553560.

    79. Jagatha B, Mythri RB, Vali S, et al. Curcumin treatment alleviates the eects ofglutathione depletion in vitro and in vivo: therapeutic implications for Parkin-sons disease explained via in silico studies. Free Radic Biol Med. 2008;44:907917.

    80. Zbarsky V, Datla KP, Parkar S, et al. Neuroprotective properties of the naturalphenolic antioxidants curcumin and naringenin but not quercetin and setin ina 6-OHDA model of Parkinsons disease. Free Radic Res. 2005;39:11191125.

    81. Wang J, Du XX, Jiang H, et al. Curcumin attenuates 6-hydroxydopamine-induced cytotoxicity by anti-oxidation and nuclear factor-kappa B modulationin MES23.5 cells. Biochem Pharmacol. 2009;78:178183.

    82. Yang S, Zhang D, Yang Z, et al. Curcumin protects dopaminergic neuron againstLPS induced neurotoxicity in primary rat neuron/glia culture. Neurochem Res.2008;33:20442053.

    83. Yu S, Zheng W, Xin N, et al. Curcumin prevents dopaminergic neuronal deaththrough inhibition of the c-Jun N-terminal kinase pathway. Rejuvenation Res.2010;13:5564.

    84. Chen J, Tang XQ, Zhi JL, et al. Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOSpathway. Apoptosis. 2006;11:943953.

    85. Rajeswari A, Sabesan M. Inhibition of monoamine oxidase-B by the polyphe-nolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model

    of Parkinsons disease induced by MPTP neurodegeneration in mice. Inam-mopharmacology. 2008;16:9699.

    86. Wang MS, Boddapati S, Emadi S, et al. Curcumin reduces alpha-synucleininduced cytotoxicity in Parkinsons disease cell model. BMC Neurosci. 2010;11:57.

    87. Pandey N, Strider J, Nolan WC, et al. Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol. 2008;115:479489.

    88. Ortiz-Ortiz MA, Moran JM, Bravosanpedro JM, et al. Curcumin enhancesparaquat-induced apoptosis of N27 mesencephalic cells via the generation ofreactive oxygen species. Neurotoxicology. 2009;30:10081018.

    89. Ortiz-Ortiz MA, Moran JM, Ruiz-Mesa LM, et al. Curcumin exposure inducesexpression of the Parkinsons disease-associated leucine-rich repeat kinase 2(LRRK2) in rat mesencephalic cells. Neurosci Lett. 2010;468:120124.

    90. van Leyen K, Kim HY, Lee SR, et al. Baicalein and 12/15-lipoxygenase in theischemic brain. Stroke. 2006;37:30143018.

    91. Chen SF, Hsu CW, Huang WH, et al. Post-injury baicalein improves histologicaland functional outcomes and reduces inammatory cytokines after experi-mental traumatic brain injury. Br J Pharmacol. 2008;155:12791296.

    92. Cheng Y, He G, Mu X, et al. Neuroprotective eect of baicalein against MPTPneurotoxicity: behavioral, biochemical and immunohistochemical prole. Neu-rosci Lett. 2008;441:1620.

    93. Mu X, He G, Cheng Y, et al. Baicalein exerts neuroprotective eects in6-hydroxydopamine-induced experimental parkinsonism in vivo and in vitro.Pharmacol Biochem Behav. 2009;92:642648.

    94. Waxman EA, Emmer KL, Giasson BI. Residue Glu83 plays a major role in nega-tively regulating a-synuclein amyloid formation. Biochem Bioph Res Commun.2010;391:14151420.

    95. Jiang M, Porat-Shliom Y, Pei Z, et al. Baicalein reduces E46K alpha-synucleinaggregation in vitro and protects cells against E46K alpha-synuclein toxicity incell models of familiar Parkinsonism. J Neurochem. 2010;114:419429.

    96. Fremont L. Biological eects of resveratrol. Life Sci. 2000;66:663673.97. Burns J, Yokota T, Ashihara H, et al. Plant foods and herbal sources of resvera-

    trol. J Agric Food Chem. 2002;50:33373340.98. Bhat KPL, Kosmeder JW, Pezzuto JM. Biological eects of resveratrol. Antioxid

    Redox Signal. 2001;3:10411064.99. Zhang F, Shi JS, Zhou H, et al. Resveratrol protects dopamine neurons against

    lipopolysaccharide-induced neurotoxicity through its anti-inammatoryactions. Mol Pharmacol. 2010;78:466477.

    100. Bournival J, Quessy P, Martinoli MG. Protective eects of resveratrol and quer-cetin against MPP+ -induced oxidative stress act by modulating markers ofapoptotic death in dopaminergic neurons. Cell Mol Neurobiol. 2009;29:11691180.

    101. Lee MK, Kang SJ, Poncz M, et al. Resveratrol protects SH-SY5Y neuroblastomacells from apoptosis induced by dopamine. Exp Mol Med. 2007;39:376384.

    102. Lu KT, Ko MC, Chen BY, et al. Neuroprotective eects of resveratrol on MPTP-induced neuron loss mediated by free radical scavenging. J Agric Food Chem.2008;56:69106913.

    103. KhanMM, Ahmad A, Ishrat T, et al. Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinsonsdisease. Brain Res. 2010;1328:139151.

    104. Bureau G, Longpre F, Martinoli MG. Resveratrol and quercetin, two naturalpolyphenols, reduce apoptotic neuronal cell death induced by neuroinamma-tion. J Neurosci Res. 2008;86:403410.

    105. Albani D, Polito L, Batelli S, et al. The SIRT1 activator resveratrol protectsSK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem. 2009;110:14451456.

    106. Pallas M, Verdaguer E, Tajes M, et al. Modulation of sirtuins: new targets forantiageing. Recent Pat CNS Drug Discov. 2008;3:6169.

    107. Pallas M, Casadesus G, Smith MA, et al. Resveratrol and neurodegenerativediseases: activation of SIRT1 as the potential pathway towards neuroprotec-tion. Curr Neurovasc Res. 2009;6:7081.

    108. Fang SC, Hsu CL, Yen GC. Anti-inammatory eects of phenolic compoundsisolated from the fruits of Artocarpus heterophyllus. J Agric Food Chem.2008;56:44634468.

    109. Su BN, Cuendet M, Hawthorne ME, et al. Constituents of the bark and twigs ofArtocarpus dadah with cyclooxygenase inhibitory activity. J Nat Prod. 2002;65:163169.

    110. Jeon SY, Kwon SH, Seong YH, et al. Beta-secretase (BACE1)-inhibiting stil-benoids from Smilax Rhizoma. Phytomedicine. 2007;14:403408.

    111. ChaoJ,YuMS,HoYS,et al.Dietaryoxyresveratrolpreventsparkinsonianmimetic6-hydroxydopamine neurotoxicity. Free Radic Biol Med. 2008;45:10191026.

    112. Xu L, ChenWF, WongMS. Ginsenoside Rg1 protects dopaminergic neurons in arat model of Parkinsons disease through the IGF-I receptor signalling pathway.Br J Pharmacol. 2009;158:738748.

    113. Rodriguez-Perez AI, Valenzuela R, Villar-Cheda B, et al. Estrogen and angio-tensin interaction in the substantia nigra. Relevance to postmenopausal Par-kinsons disease. Exp Neurol. 2010;224:517526.

    114. Sawada H, Shimohama S. Estrogens and Parkinson disease: novel approach forneuroprotection. Endocrine. 2003;21:7779.

    Nutrition Reviews Vol. 70(7):373386 385

  • 115. Chen XC, Zhou YC, Chen Y, et al. Ginsenoside Rg1 reduces MPTP-induced sub-stantia nigra neuron loss by suppressing oxidative stress. Acta Pharmacol Sin.2005;26:5662.

    116. Ma ZC, Gao Y, Wang YG, et al. Ginsenoside Rg1 inhibits proliferation of vascularsmooth muscle cells stimulated by tumor necrosis factor-alpha. Acta Pharma-col Sin. 2006;27:10001006.

    117. Leung KW, Yung KKL, Mak NK, et al. Neuroprotective eects of ginsenoside-Rg1in primary nigral neurons against rotenone toxicity. Neuropharmacology.2007;52:827835.

    118. Gao QG, Chen WF, Xie JX, et al. Ginsenoside Rg1 protects against 6-OHDA-induced neurotoxicity in neuroblastoma SK-N-SH cells via IGF-I receptor andestrogen receptor pathways. J Neurochem. 2009;109:13381347.

    119. Ge KL, Chen WF, Xie JX, et al. Ginsenoside Rg1 protects against 6-OHDA-induced toxicity in MES23.5 cells via Akt and ERK signaling pathways. J Ethno-pharmacol. 2010;127:118123.

    120. Xu H, Jiang H, Wang J, et al. Rg1 protects the MPP+-treated MES23.5 cells viaattenuating DMT1 up-regulation and cellular iron uptake. Neuropharmacology.2010;58:488494.

    121. Leppa S, Bohmann D. Diverse functions of JNK signaling and c-Jun in stressresponse and apoptosis. Oncogene. 1999;18:61586162.

    122. Wang J, Xu HM, Yang HD, et al. Rg1 reduces nigral iron levels of MPTP-treatedC57BL6 mice by regulating certain iron transport proteins. Neurochem Int.2009;54:4348.

    123. Ma Y, Sullivan JC, Schreihofer DA. Dietary genistein and equol (4`, 7 isoavan-diol) reduce oxidative stress and protect rats against focal cerebral ischemia.Am J Physiol Regul Integr Comp Physiol. 2010;299:R871R877.

    124. Azadbakht L, Kimiagar M, Mehrabi Y, et al. Dietary soya intake alters plasmaantioxidant status and lipid peroxidation in postmenopausal women with themetabolic syndrome. Br J Nutr. 2007;98:807813.

    125. Cyr M, Calon F, Morissette M, et al. Estrogenic modulation of brain activity:implications for schizophrenia and Parkinsons disease. J Psychiatry Neurosci.2002;27:1227.

    126. Baluchnejadmojarad T, Roghani M, Nadoushan JMR, et al. Neuroprotectiveeect of genistein in 6-hydroxydopamine hemi-parkinsonian rat model. Phy-tother Res. 2009;23:132135.

    127. Huang YH, Zhang ZQ. Genistein reduced the neural apoptosis in the brain ofovariectomised rats by modulating mitochondrial oxidative stress. Br J Nutr.2010;104:17.

    128. Kaul S, Anantharam V, Yang Y, et al. Tyrosine phosphorylation regulates theproteolytic activation of protein kinase C in dopaminergic neuronal cells. J BiolChem. 2005;280:2872128730.

    129. Miller JW, Selhub J, Nadeau MR, et al. Eect of L-dopa on plasma homocys-teine in PD patients: relationship to B-vitamin status. Neurology. 2003;60:11251129.

    130. Zesiewicz TA, Wecker L, Sullivan KL, et al. The controversy concerning plasmahomocysteine in Parkinson disease patients treated with levodopa alone orwith entacapone: eects of vitamin status. Clin Neuropharmacol. 2006;29:106111.

    131. Lamberti P, Zoccolella S, Armenise E, et al. Hyperhomocysteinemia in L-dopatreated Parkinsons disease patients: eect of cobalamin and folate administra-tion. Eur J Neurol. 2005;12:365368.

    132. Nagayama H, Hamamoto M, Ueda M, et al. The eect of ascorbic acid on thepharmacokinetics of levodopa in elderly patients with Parkinson disease. ClinNeuropharmacol. 2004;27:270273.

    133. Fernandez N, Carriedo D, Sierra M, et al. Hydrosoluble ber (Plantagoovata husk) and levodopa II: experimental study of the pharmacokineticinteraction in the presence of carbidopa. Eur Neuropsychopharmacol. 2005;15:505509.

    Nutrition Reviews Vol. 70(7):373386386