NUTRACEUTICALS AND THEIR PREVENTIVE OR POTENTIAL THERAPEUTIC VALUE IN PARKINSON'S DISEASE
 
   

Nutraceuticals and Their Preventive
or Potential Therapeutic Value
in Parkinson's Disease

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:
   Frankp@chiro.org
 
   

FROM:   Nutrition Reviews 2012 (Jul);   70 (7):   373–386

Chao J, Leung Y, Wang M, Chang RC.

Laboratory of Neurodegenerative Diseases,
Department of Anatomy,
LKS Faculty of Medicine,
The University of Hong Kong,
Pokfulam, Hong Kong SAR, China.


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.


From the Full-Text Article:

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 amajor 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 pesticides include paraquat, organophosphates, and rotenone. [3] MPTP exposure has been found to induce both loss of dopaminergic neurons and clinical parkinsonism. Similarly, rotenone and paraquat, when applied to experimental animals, have been found to induce loss of dopaminergic neurons and typical parkinsonism. [4] As potential etiological factors of PD, environmental chemicals may interact with gene expression and modulate expression of mutated genes in humans.Thus, genetic analysis of patients with PD has become an important research theme in PD.

A small percentage of PD cases are attributed to single gene defects. Thus far, genetic studies have identified more than 10 genes that cause familial PD. The functions of these genes, along with associated clinical features, are listed in Table 1. [5, 6]


Table 1.   Gene identification in Parkinson's disease.




PATHOLOGICAL FACTORS ASSOCIATED WITH PARKINSON'S DISEASE

PD is defined pathologically by the progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta accompanied by the presence of intracellular Lewy bodies.Parkinsonism, along with parkinsonian syndrome, 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 bears no implication of disease mechanism, while PD refers to the pathology described above. The exact mechanisms of PD are not yet fully understood, although several factors, including protein misfolding, oxidative stress, and mitochondrial dysfunction, have been reported.

Numerous studies indicate a causal role of misfolded proteins such as beta-amyloid and a-synuclein inAD and PD, as misfolding results in accumulation of the protein either extra- or intracellularly. [7] If chaperones fail to restore misfolded proteins, the ubiquitin proteasome system and autophagy will subsequently clear the misfolded proteins. [8] Both mutation and aggregation of a-synuclein can cause parkinsonism, but mutation of a-synuclein is rarely found in patients with sporadic PD. [9]

Unique biochemical features of the SN render it more vulnerable to oxidative stress when compared with other parts of the brain. In particular, the SN has a uniquely high iron content.Dopamine can be oxidized by monoamine oxidase B (MAO-B) to form hydroxyl free radicals in the presence of ferrous iron. The combined effects result in enormous amounts of hydroxyl free radicals, leading to severe damage of the dopaminergic neurons of the SN. These pathological events suggest that oxidative stress is the most important pathological factor for the initiation and progression of PD. [10]

Indeed, the SNs of PD patients have been found to show elevated levels of oxidative stress.Youdim and Riederer [11] reported that lipid-peroxidation-promoting substances such as ferrous iron are found in high levels in the SN of postmortem PD brain, concomitant with decreased levels of antioxidants. Similar results were obtained by a study investigating the level of hydroxynonenal adducts, which are products of lipid peroxidation. [12] Elevated levels of lipid peroxidation have been found in the SN region of the brain and in erythrocytes from blood samples of PD patients. [13]

Numerous studies suggest that impairment of mitochondrial function is also involved in the pathogenesis of PD.Mitochondrial function is closely related to oxidative stress because mitochondria produce ATP by oxidative phosphorylation. During ATP production, mitochondria may produce superoxide radicals as by-products. Defects of the electron transport chain can result in the failure of energy metabolism, increased free-radical-mediated damage, and activation of downstream cell death pathways. [14–16] In the early 1980s, contamination of MPTP in heroin was found to cause parkinsonism in drug abusers. [17] Since then, MPTP has been used extensively to induce neurotoxic experimental PD. The active form of MPTP is metabolized in the mitochondria of astrocytes in the SN to form MPP+ and is then transferred to inhibit complex I of the electron transport chain in neurons, leading to ATP depletion and accumulation of reactive oxygen species (ROS). [18] Elevated mitochondrial ROS levels result in mitochondrial DNA mutations, proteins/ lipids perturbation and can further affect redox signaling pathways. [19] Another widely used neurotoxin, 6-OHDA, induces pathological events similar to those seen in experimental PD. [20] Numerous studies have shown that food components and nutritional substances can prevent or delay the progression of PD by protecting mitochondrial function. [21] This further supports the role of mitochondrial impairment as a major pathological factor in PD. [22–24]



TREATMENT FOR PATIENTS WITH PARKINSON'S DISEASE

Although PD was first diagnosed almost two centuries ago, a cure has yet to be found. Current treatments are mainly categorized into symptom-relieving drugs and surgical treatments. L-dopa, dopamine agonists (pramipexole, bromocriptine, pergolide, ropinirole, piribedil, cabergoline, apomorphine, and lisuride) and MAO-B inhibitors (selegiline and rasagiline) are examples of symptom-relieving drugs, while deep brain stimulation, implantation of embryonic dopaminergic cells, and gene therapy have been applied as surgical treatments for PD patients. These treatments only aim to improve the quality of life by attenuating motor or nonmotor symptoms of PD. As the global population ages, the need to develop a disease-modifying drug for PD is becoming increasingly urgent.

Existing PD treatments have undesirable effects. For example, L-dopa, a commonly used symptom-relieving drug for PD, has various side effects because 95–99% of it is metabolized to dopamine in the body in places other than the dopaminergic neurons in the SN.For this reason, dopa decarboxylase inhibitors (e.g., carbidopa and benserazide) and COMT enzyme inhibitors (e.g., tolcapone and entacapone) are prescribed in combination with L-lopa to enhance its effect. Discontinuous delivery of 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 a transdermal delivery system, both of which have been applied in clinical settings for the past two decades. [5, 6]



POTENTIAL NEUROPROTECTIVE EFFECTS OF NUTRACEUTICALS

Combining the words “nutrition” and “pharmaceutical,” the word“nutraceuticals” refers to foods or food products that reasonable clinical evidence suggests may provide health and medical benefits, including for prevention and treatment of disease. Such products may be categorized as dietary supplements, specific diets, herbal products, or processed foods such as cereals, soups, and beverages. Dietary supplements can be extracts or concentrates and are found in many forms, including tablets, capsules, liquids, and powders. Vitamins, minerals, herbs, or isolated bioactive compounds are only a few examples of dietary ingredients in the products. Functional foods are designed as enriched foods close to their natural state, providing an alternative to dietary supplements manufactured in liquid or capsule form.

It is generally accepted that neuroprotection prevents neurons from succumbing to damages by different insults. Nutraceuticals can provide neuroprotection via a wide range of proposed mechanisms, such as scavenging of free radicals and ROS, chelation of iron, modulation of cell-signaling pathways, and inhibition of inflammation. [25] Neuroprotection can prevent and impede the progression of PD as well as the loss of dopaminergic neurons. In the following section, the neuroprotective effects of selected dietary supplements and functional foods are reviewed and discussed. In addition, several relevant therapeutic effects are evaluated.



ANTIOXIDANT VITAMIN SUPPLEMENTS (VITAMINS C AND E)

Antioxidant vitamin supplements such as vitamin C, vitamin E (or tocopherol), and beta-carotene are common forms of nutraceuticals. [26] A cross-sectional study found that vitamin E supplements are popular in PD patients, while epidemiological studies have shown that consuming foods rich in vitamins C and E are associated with a lower risk of developing PD. [27] However, it should be noted that these studies are not specific to individual antioxidant nutrients; rather, it is the foods rich in these nutrients that are studied.

      Potential Neuroprotective Effects

An early study has suggested a protective effect of these two antioxidative vitamins on PD patients.28 In an openlabel trial, high doses of vitamins C and E were administered to patients in the early stage of PD. It was found that patients who took antioxidant vitamins had a 2.5- to 3-year delay in receiving L-dopa treatment compared with those of Dr. CM Tanner, who did not treat patients with vitamins, as reported by Fahn. [28] Treatment was delayed from 40 months to 72  6.5 months for those PD patients who started taking the vitamins before 54 years of age, and from 24 months to 63  3.9 months for those who started the vitamins after 54 years of age. Although the placebo effect might be at play here, the delay of onset of parkinsonism was remarkably significant. Another report showed that vitamin C at 10 mM can reduce neurotoxicity elicited by dopamine metabolism. [28]

An important double-blind and placebo-controlled clinical study, the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) by the Parkinson Study Group, showed that vitamin E supplementation was not able to delay the need for introducing L-dopa therapy. [30] However, as pointed out in a commentary for this study, the trial did not exclude the possibility that nutritional supplements may delay progression of PD by preventing loss of dopaminergic neurons. [31] A contradicting report showed that 9.8 IU/day of vitamin E intake from the diet may be beneficial. [32] A meta-analysis produced similar results, showing that dietary intake of vitamin E in moderate amounts may be neuroprotective. High intake of vitamin C in the form of a supplement was not significantly protective, with no association found between vitamin C intake and risk of PD. [33]

      Mechanisms of Action

Antioxidant vitamins have a putative role in reducing the oxidative damage in SN dopaminergic neurons in progressive disease. [34] Vitamin C has been proven in vitro to be a major free-radical scavenger in the cytosol, while tocopherols act as a major lipid-soluble antioxidant to prevent lipid peroxidation in membranes. Both vitamins also act in a synergistic manner whereby vitamin C can reduce oxidized vitamin E to restore its antioxidative function. [35] Thus, supplemental vitamins can be useful in prevention or in delaying progression of PD by reducing oxidative stress.



VITAMIN D

      Potential Neuroprotective Effects

In 2007,Newmark and Newmark [36] proposed that vitamin D deficiency had a significant role in the development and progression of PD. Vitamin D has been found to attenuate 6-OHDA-induced and MPP+-induced neurotoxicity, while vitamin D receptor knockout mice show motor defect.Moreover, the levels of vitamin-D-binding protein have been proposed as one of the biomarkers for PD. [37–39]

It has been debated that vitamin D inadequacy in PD patients is a result of reduced physical activity and exposure to sunlight, rather than a causal factor in PD progression. However, the results of a recent longitudinal study by Knekt et al. [40] oppose this view.A large sample of Finnish adults aged 30 years or older was selected from 1978 to 1980, and blood serum samples were examined. Occurrences of PD were recorded in a 29-year follow-up period. In 2002, serum levels of vitaminDweremeasured, and results showed that subjects with higher serum vitamin D levels had a significantly lower risk of developing PD. [40] These data suggest that vitamin D levels could be used as a predictive indicator of PD risk.

      Mechanisms of Action

The SN is one of the regions in the brain containing high levels of vitamin D receptors and 1a-hydroxylase, [40] the enzyme responsible for the biological activation of vitamin D. Hence, vitamin D may be involved in a number of signaling pathways, and several mechanisms may be responsible for the neuroprotective effects of vitamin D.

In animal studies, vitamin D was found to upregulate glial cell line-derived neurotrophic factor levels. [37] Glial cell line-derived neurotrophic factor has been shown to be antiparkinsonian in animal and in vitro studies. It can promote the outgrowth of dopaminergic axons in striatal neurons in a region-specific manner and can even rescue SN neurons from 6-OHDA toxicity.41 In addition, vitamin D can increase glutathione levels, regulate calcium homeostasis, exert anti-apoptotic and immunomodulatory effects, reduce nitric oxide synthase, and regulate dopamine levels. [42, 43]



COENZYME Q10

      Potential Neuroprotective Effects

Coenzyme Q10 (CoQ10 or ubiquinone) is a popular commercially available dietary supplement (Figure 1). It has been recognized as a neuroprotective agent in the prevention and treatment of PD. [44] CoQ10 has been demonstrated to prevent the loss of dopaminergic neurons in MPTP-induced neurotoxicity and parkinsonism. [45, 46] In a placebo-controlled, randomized, double-blind study involving 80 patients with early-stage PD, patients in the treatment group were found to have less disability, as evaluated for over 16 months using the Unified Parkinson Disease Rating Scale. It should be noted that the effects of CoQ10 were dose dependent. The group receiving 1,200 mg/day, which was the highest dose among the different groups, exhibited a 44% reduction in functional decline compared with the placebo group. [47] In another study, amild symptomatic benefit was observed using the Farnsworth-Munsell 100 Hue test. The authors suggested that an oral supplement of CoQ10 could achieve a moderate beneficial effect, but not a great neuroprotective effect. [48] From these reports, there is no conclusion about whether the effect of CoQ10 on PD is neuroprotective or merely symptom relieving.

      Mechanisms of Action

CoQ10 is a fat-soluble and vitamin-like quinone found abundantly in liver and the brain. [49] CoQ10 is particularly relevant to mitochondrial dysfunction because of its unique electron-accepting property, which allows it to bridge mitochondrial complex I with other complexes. CoQ10 plays an important role in maintaining proper transfer of electrons in the electron transport chain of mitochondria and, thus, in the production of ATP as well. As a result, CoQ10 has a protective effect on dopaminergic neurons in the SN. In addition, it is a potent antioxidant and can exert its antioxidant effect by reducing the oxidized form of alpha-tocopherol, [50] which is important in the prevention of lipid peroxidation.

CREATINE

      Potential Neuroprotective Effects

Creatine has also been investigated for its possible role in the treatment and prevention of PD (Figure 1). In a study using MPTP in a PD mouse model, a diet supplement of 1% creatine reduced loss of dopaminergic neurons in the SN.51A placebo-controlled and randomized pilot trial for a 2-year period showed that creatine can improve mood and reduce the dosages required for dopaminereplacement therapy in the treated group. [52]

      Mechanisms of action

Creatine is considered to be neuroprotective due to its ability to counter ATP depletion by increasing intracellular phosphocreatine levels. [51] Phosphocreatine is a key player in the maintenance of ATP levels, which in turn are important in synaptic activity and skeletal muscle functions. [53, 54]


Figure 1.   Chemical structure of
(a) coenzyme Q10 and
(b) creatine.





UNSATURATED FATTY ACIDS

      Potential Neuroprotective Effects

While unsaturated fatty acids were reported to reduce the risk of developing PD, [55] results from past epidemiological and retrospective studies were inconsistent. To study the relationship, a prospective study was conducted in two cohorts, the Health Professional Follow-up Study and the Nurses’ Health Study. [56] The authors concluded that if saturated fatty acids are replaced by polyunsaturated fatty acids (PUFAs), the risk of developing PD may be reduced. In another large prospective population-based cohort study, the Rotterdam Study, the authors investigated the relationship between dietary unsaturated fatty acids and the risk of developing PD. [55] In contrast to the previous study, they showed no relationship between the level of saturated fatty acids and the risk of developing PD. In addition to the above studies, the results of a recent investigation on omega-3 PUFAs suggest a neuroprotective effect of omega-3 PUFAs against dopamine loss and an inhibitory effect against the formation of dihydroxyphenylacetic acid in MPTP-induced parkinsonism in mice. [57] This positive result should encourage future studies on the possible mechanism of PUFAs.

      Mechanisms of Action

PUFAs such as linoleic acid, alpha-linolenic acid, and docosahexaenoic acid can be components of cell membrane and precursors of signaling molecules. [58] Some of these PUFAs cannot be synthesized in the human body and must be obtained from food.Monounsaturated fatty acids (MUFAs) can also reduce cholesterol and triacylglycerides in plasma. [59] Impaired brain function is strongly associated with deficiency of MUFAs and PUFAs. Endogenous cannabinoids derived from MUFAs are important modulators for dopaminergic neurons in the basal ganglia. [60] A report has shown that fatty acid composition in the brain is highly correlated with the intake of dietary fatty acids. [61] All these facts justify further study of the relationship between the intake of unsaturated fatty acids and the risk of developing PD.



NATURAL SOURCES OF L-DOPA

      Potential Neuroprotective Effects

To date, natural L-dopa has been found in several plants belonging to Mucuna genus, such as Mucuna pruriens (velvet bean or mucuna, the seeds of which, in 1937, were found to contain L-dopa), Stizolobium deeringianum, and Vicia faba (broad bean, in which L-dopa was identified in 1913). M. pruriens (called “atmagupta” in India) is a climbing legume endemic in tropical regions that include India and Central and South America. The plant has been documented in Ayurvedic medicine to treat a neurological disorder bearing symptoms similar to those of PD and up to 10% of the plant’s volume is L-dopa. [62] In recent years, velvet bean seed extract has been used for the treatment of PD in India. [63]

Several open-label studies with sample sizes ranging between 18 and 60 patients prescribed mucuna seed powder extract at mean doses of 45 g/day (containing about 1,500 mg L-dopa). Significant improvements in parkinsonism were reported and better tolerability was found compared with standard L-dopa treatment alone. [64–66] In a recent double-blind study involving eight PD patients, the anti-Parkinsonian effect, tolerability, and L-dopa pharmacokinetic profile were compared between the mucuna seed formulation and the commercial L-dopa. [67] The results showed that the effects of 30 g of M. pruriens formulation were superior to those of the standard single doses of 200/50 mg L-dopa/carbidopa. The bean powder enabled a more rapid onset of action in patients and had a slightly longer duration of therapeutic response. Moreover, severe dyskinesia or peripheral dopaminergic adverse events were not found in the mucuna-treated patients. It is suggested that the mucuna formulation may have greater bioavailability, perhaps as a result of synergistic properties of different compounds in the seed extract.

      Mechanisms of Action

Most in vitro studies on natural L-dopa sources focus on mucuna. In 2004, Manyam et al. [68] showed that mucuna seed powder contained significant amounts of two neuroprotective agents, namely nicotine adenine dinucleotide (NADH) and CoQ10. Both agents protect neurons against 6-OHDA toxicity by counteracting the inhibition of mitochondrial complex I activity.NADHis also known to increase dopamine levels via the upregulation of tyrosine hydrolase.

Mucuna seed powder has also been found to protect neurons against plasmid DNA and genomic DNA damage caused by a combination of L-dopa and divalent copper ions. [69, 70] Mucuna seed powder protects neurons against this type of damage by chelating the divalent copper ions present, preventing them from interacting with L-dopa to produce



POLYPHENOLIC COMPOUNDS

Polyphenolic compounds, or polyphenols, are products of secondary plant metabolism and are widely distributed in the plant kingdom. Polyphenolic compounds refer to a range of substances that possess an aromatic ring bearing more than one hydroxyl group.More than 8,000 phenolic structures have been identified. Polyphenols are generally divided into hydrolyzable tannins (gallic acid esters of glucose and other sugars) and phenylpropanoids, such as lignins, flavonoids, and condensed tannins.

Polyphenols can elicit antioxidant, antiinflammatory, anticarcinogenic, antimutagenic, and antithrombotic effects. [71] The neuroprotective effects of the major polyphenolic compounds in green tea, black tea, coffee, curry, and Scutellaria baicalensis, an herb used in traditional Chinese medicine, are reviewed below.

EGCG in green tea

Potential Neuroprotective Effects. Numerous studies suggest green tea may confer health benefits due to its pharmacological and biochemical properties. Epidemiological studies have shown an inverse relationship between tea consumption and the risk of developing PD. There are several experimental studies showing neuroprotective effects of green tea on MPTP-induced parkinsonism in mouse models and on cell injury in pheochromocytoma PC12 cells treated by 6-OHDA. [72] Many of the beneficial effects of green tea are attributed to its abundant polyphenol content, mainly the flavans called catechins (Figure 2). [73] There are numerous catechins 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 of tea polyphenols and reported the following benefits: free-radical scavenging and anticarcinogenic, antiinflammatory, and antiangiogenic effects.

      Mechanisms of Action

Different mechanisms have been proposed for the neuroprotective activity of EGCG in PD. The study conducted by Levites et al. [75] was the first to demonstrate the neuroprotective activity of both green tea extract (0.5 and 1 mg/kg) and EGCG (2 and 10 mg/ kg) on MPTP-induced parkinsonism in animal models. It is possible that the neuroprotective effects are mediated by iron-chelating activities and free-radical-scavenging activities possessed by the catechol group. Since green tea catechins can pass through the blood-brain barrier, they can act as both ROS scavengers and iron chelators to clear the redox active ferrous iron deposited in the SN, reducing the iron-induced oxidative stress that can lead to neuronal death.

The putative neuroprotective effects of green tea catechins also may be mediated via other mechanisms. Mandel et al. [73] and Levites et al. 76 summarized the neuroprotective mechanisms of green tea catechins as regulation of protein kinase C activity and induction of endogenous antioxidant defense systems. A recent experimental study using the 6-OHDA rat model of PD also suggests that green tea catechins protect the SN dopaminergic neurons through modulation of the ROS-NO pathway. [77] It appears there is considerable evidence to support the putative neuroprotective effects of green tea.Nonetheless, much of the evidence was derived from experimental and animal studies, while evidence from large prospective studies or case-control studies specific to green tea catechins rather than to general tea consumption is limited. In contrast to other reports showing beneficial effects of green tea, the prospective cohort study of the Singapore Chinese Health Study [78] showed no relationship between green tea consumption and the risk of developing PD if caffeine intake was excluded. Therefore, more studies of green tea consumption in humans and the risk of developing PD are required to verify the possible protective effect of green tea.

Curcuminoids in curry

Potential neuroprotective effects. Curcumin (1,7-bis[4- hydroxy 3-methoxy phenyl]-1,6-heptadiene-3,5-dione) is a polyphenolic flavonoid that constitutes approximately 4% of turmeric, which has a long history of use in traditional Asian diets and herbal medicines (Figure 2). Curcumin is the principal curcuminoid in turmeric. The other two curcuminoids are desmethoxycurcumin and bisdesmethoxycurcumin.Curcuminoids, rather than curcumin alone, are commercially available and are generally used in experimental studies. The bioactive effects of curcuminoids have often been attributed to curcumin, as the curcumin content of curcuminoids reaches up to 80%.

      Mechanisms of Action

Like other polyphenolic compounds such as caffeic acid, EGCG, and resveratrol, curcumin is well known for its powerful antioxidant properties. Jagatha et al. [79] reported that curcumin treatment of mice and of dopaminergic neurons in cell cultures attenuated oxidative stress by restoring glutathione levels, thereby protecting neurons against protein oxidation and preserving mitochondrial complex I activity. The reduction of 6-OHDA-induced neurotoxicity in MES 23.5 cells and in a rat model of PD has been attributed to the antioxidant properties of curcumin. [80] In addition, curcumin’s direct modulation of 6-OHDA-induced nuclear factor-kappa B (NF-kB) translocation confers neuroprotective effects in dopaminergic neuronal cells of the MES 23.5 cell line. [81]

Curcumin has also been found to exhibit antiinflammatory properties. In primary cultures of rat mesencephalic neuronal/glial cells, curcumin inhibited lipopolysaccharide (LPS)-induced morphological changes of microglia and dramatically reduced LPSinduced production of many proinflammatory factors and their gene expressions. LPS-induced activation of transcription factors, such as NF-kB and activator protein-1, were also attenuated by curcumin treatment. [82]

In addition, curcumin has been found to prevent MPTP/MPP+-induced neurotoxicity in C57BL/6N mice, SH-SY5Y cells, and PC12 cells by targeting the JNK, the Bcl-2-mitochondria, and the ROS-iNOS (inducible nitric oxide synthase) pathways. [83, 84] Systemic administration of curcumin (80 mg/kg i.p.) and its metabolite tetrahydrocurcumin (60 mg/kg i.p.) significantly reversed MPTP-induced depletion of DA and DOPAC (3,4- dihydroxy phenyl acetic acid) in mice. The authors concluded that the reversion may be, in part, due to the inhibition of MAO-B activity by these compounds. [85]

Furthermore, both overexpression and abnormal accumulation of aggregated alpha-synuclein (AS) have been found to be closely linked to PD. Recent studies revealed that curcumin could inhibit aggregation of AS in cell-free conditions and in a cellular model of A53T-AS overexpression. [86, 87]

Ortiz-Ortiz et al., [88] however, called for re-evaluation of the potential of curcumin as a therapeutic agent in neurodegenerative diseases. In contrast to findings reported previously by others, Ortiz-Ortiz et al. [89] surprisingly found that exposure of N27 mesencephalic cells to 10 nM curcumin synergistically enhanced paraquatmediated apoptosis. A very recent study from the same group found that exposure of rat mesencephalic cells to 10 nM curcumin induced the expression of LRRK2 in mRNA and protein levels, although there was no effect on other PD-related genes like AS and parkin. Overexpression of LRRK2 is strongly associated with the pathological inclusions found in PD. Taken together, the findings for curcumin remain controversial and await further experimental and clinical studies.

Baicalein

      Potential Neuroprotective Effects

Baicalein is a flavonoid extracted from the root of Scutellaria baicalensis, a traditional Chinese herb commonly known as Huang Qin. Baicalein has been shown to be a potent antioxidant in rat primary neurons (Figure 2). [90] Another study in rats also showed anti-inflammatory properties of baicalein in experimental traumatic brain injury. [91] Baicalein was found to be neuroprotective in several experimental models of PD, including MPTP-induced neurotoxicity and 6-OHDA-induced neurotoxicity. [92, 93] It has also been shown to inhibit fibrillization of AS. [94] In a recent study, baicalein attenuated depolarization of mitochondria and proteasome inhibition in PC12 cells induced by the E46K mutation, an AS mutation linked to familial parkinsonism. [95] The mechanisms underlying the neuroprotective effects of baicalein, however, remain unclear.



STILBENES

Stilbenes are a class of antioxidants sharing the same chemical skeleton of a diarylethene, which is a hydrocarbon consisting of a trans/cis ethene double bond substituted with a phenyl group on both carbon atoms of the double bond. The name “stilbene” was derived from the Greek word “stilbos,” which means “shining.” Many stilbenes and their derivates (stilbenoids) are naturally present in plants (dietary fruits or herbs).

Resveratrol

      Potential Neuroprotective Effects

The most widely investigated stilbene is resveratrol (3, 4', 5-transtrihydroxystilbene, RES, Figure 3), a phytoalexin found in plants such as grapes, peanuts, berries, and pines. [96] RES is synthesized in these plants to counteract various environmental injuries, such as UV irradiation and fungal infection. RES is reported to be one of the active agents in Itadori tea, which has been used as a traditional medicine in China and Japan, mainly for treating heart disease and stroke. [97] Epidemiological studies reporting the inverse association between moderate consumption of red wine and the incidence of coronary heart disease have stimulated investigations on the cardioprotective activity of RES. [98] In recent years, numerous studies have shown that RES can protect dopaminergic neurons against toxicity induced by LPS, DA, or MPP+. [99–101] The neuroprotective effects of RES have also been reported in 6-OHDAlesioned rats and in mouse models of MPTP-induced neuronal loss. [102, 103]

      Mechanisms of Action

The underlying mechanisms of neuroprotection by RES include the inhibition of NADPH oxidase and the suppression of proinflammatory genes such as interleukin 1-a and tumor necrosis factor-a triggered by LPS. [99, 104] Pretreatment with RES reduced apoptosis in PC12 cells by modulating mRNA levels and protein expression levels of BAX and Bcl-2 in vitro. [100] RES may stimulate SIRT1 in 6-OHDA-triggered SK-N-BE cells, as indicated by the loss of protection in the presence of the SIRT1 inhibitor sirtinol, a loss that also occurred when SIRT1 expression was downregulated by siRNA approach. [105–107] In addition, RES exhibits neuroprotective effects on MPTP-induced motor coordination impairment, hydroxyl radical overloading, and neuronal loss through free-radical-scavenging activity. [102]

Oxyresveratrol

      Potential Neuroprotective Effects

Recent studies have found that RES may not be the most effective neuroprotective agent. Investigations on the differential bioactivities of RES and oxyresveratrol (OXY) (2, 32, 4, 52-trans-trihydroxystilbene, Figure 3) have shownOXY to be a more effective neuroprotective agent. OXY is found in the heartwood or fruit of Artocarpus heterophyllus, Artocarpus lakoocha, Artocarpus gomezianus, and Artocarpus dadah, in the wood or fruit of mulberry trees (Morus australis,Morus alba L.), in the fruit of Melaleuca leucadendron, in rhizomes of Smilacis chinae, and in the Egyptian herb Schoenocaulon officinale.

      Mechanisms of Action

In vivo and in vitro studies have shown anti-inflammatory effects of OXY, particularly OXY isolated from Artocarpus heterophyllus, Artocarpus dadah, or mulberry wood. [108, 109] OXY can also reduce the production of beta-amyloid by inhibiting b-secretase 1. [110] OXY has been demonstrated to protect against 6-OHDAinduced toxicity in SH-SY5Y cells by reducing the release of lactate dehydrogenase and caspase-3 specific activity. [111] Analysis by high-performance liquid chromatography showed that OXY readily penetrates into neurons, thereby suppressing the level of intracellular ROS by its potent free-radical-scavenging activity. OXY was also found to upregulate SIRT1 levels, indicating that the neuroprotective properties of SIRT1may be attributable to its activation. [111]



PHYTOESTROGENS

It has been known that the incidence of PD is lower in women than in men (using age controls), indicating a protective effect of estrogen or its derivatives. [112] The incidence of PD is also lower in premenopausal women than in postmenopausal women. [113] The neuroprotective effects of estrogen have been shown in many studies, including upregulation of Bcl-2 and brain-derived neurotrophic factor. [114] However, numerous side effects discourage women from receiving hormone replacement therapy. Phytoestrogens, obtained through either the diet or supplements, provide an alternative to traditional hormone replacement therapy without some of the reported side effects; this will be discussed in the following section.

Phytoestrogens are a group of substances that are found naturally in plants and possess a common chemical structure similar to that of estradiol. Major food sources of phytoestrogens include soy products, nuts, and grains. Two types of phytoestrogens are discussed below.

Ginsenoside Rg1

      Potential Neuroprotective Effects

Ginsenosides are a class of molecules extracted from several species of ginseng. Ginseng has a long history in traditional Chinese medicine, Indian herbal medicine, and the medicine of other Asian cultures, and it is well known for its antiaging effects. Rg1 is a ginsenoside isolated from the root of Panax ginseng. It is one of the relatively well-studied ginsenosides (Figure 4). In vivo, Rg1 can attenuate 6-OHDA neurotoxicity, MPTP-induced neurotoxicity, and oxidative stress. [112, 115] It can also suppress tumor proliferation. [116] In vitro studies have shown that Rg1 can attenuate rotenone toxicity. [117]

      Mechanisms of Action

Ginsenoside Rg1 has been found to regulate several signaling pathways, which may explain its neuroprotective effects. The signaling pathways modulated by ginsenoside Rg1 include PI3K/Akt, ERK, JNK, ROS-NFkB, IGF-1 receptor signaling pathways, and estrogen receptor pathway. [115, 118–120]

In 2005,Chen et al. [115] tested the effects of Rg1 against MPTP-induced neurotoxicity in mice. Results showed that Rg1 was able to reduce neuronal loss caused by MPTP toxicity through two possible mechanisms. First, Rg1 prevented the reduction of glutathione. Second, Rg1 attenuated phosphorylation of c-Jun, as JNK signaling can be proapoptotic. [115, 121] A third mechanism was proposed by Wang et al. [122] in 2009. By iron staining, the authors showed, in a mouse model of MPTP toxicity, that elevated iron levels in the SN were linked to neuronal death. Rg1 prevented this elevation of iron levels by regulating the expression of iron transport proteins such as ferroportin 1 and divalent metal transport 1. [122]

Rg1 is also beneficial to the maintenance of mitochondrial functions. In the presence of rotenone, Rg1 restored depleted mitochondrial membrane potential. [117] Antiapoptotic effects included inhibition of cytochrome c release and activation of the PI3K/Akt cell survival pathway, resulting in enhanced inhibition of Bad protein expression. [117] Upon blocking the glucocorticoid receptor with an antagonist, these effects were blocked, indicating that Rg1 mediates its effects through the glucocorticoid receptor. [117]

Genistein

      Potential Neuroprotective Effects

Soy and peanuts are rich dietary sources of the phytoestrogen genistein, which has been found to be the primary circulating soy isoflavone (Figure 4). [123] In fact, dietary soy is widely used as an alternative to traditional hormonal replacement therapy. In 2007, a study was conducted byAzadbakht et al. [124] to find the effects of dietary soy on postmenopausal women with metabolic syndrome. Compared with normal subjects, the postmenopausal women had reduced plasma levels of malondialdehyde, an oxidative stress marker. Numerous studies in rats have shown that treatment with genistein isolated from plant sources results in similar antioxidative effects and antiapoptotic effects.

      Mechanisms of Action

Many studies have shown that genistein binds to estrogen receptors in the central nervous system. The estrogen receptor b has been found to have a particularly high binding affinity for genistein. [126] Upon binding to the estrogen receptor, the genisteinreceptor complex acts as a transcriptional activator to upregulate antioxidative and antiapoptotic genes. [123, 126]

The antioxidative effects of genistein have been attributed to its ability to increase the levels of malondialdehyde, superoxide dismutase, and monoamine oxidase. [124, 127] On the other hand,Kaul et al. [128] concluded that genistein specifically attenuated the generation of ROS, but not oxidative stress. [128] They conducted an experiment testing the effect of genistein on hydrogen-peroxideinduced cell death in rat mesencephalic dopaminergic neurons known as N27 cells. While no antioxidative mechanism was suggested, the authors showed that genistein acted as a tyrosine kinase inhibitor, thereby attenuating the activation of protein kinase C gamma and its downstream proapoptotic effects. [128]

In addition, it has been proposed that genistein may be able to regulate activity of dopaminergic neurons because estradiol has been shown to play a role in regulation of the neurotransmitter in animal studies. [125] A recent study testing the effects of genistein treatment prior to intrastriatal 6-OHDA lesions in rats is in line with this hypothesis. It was found that genistein pretreatment attenuated rotational behavior in rats, a symptom of parkinsonism. [126]



POTENTIAL APPLICATIONS OF NUTRACEUTICALS IN CURRENT PD THERAPY

The potential benefits of nutraceuticals in PD may extend from prevention to the delay of disease progression. Furthermore, dietary supplements or functional foods may reduce the side effects of current treatments or enhance the bioavailability of L-dopa.

B vitamins and hyperhomocysteinemia

Numerous studies have demonstrated that treatment with L-dopa in PD patients induces high levels of homocysteine (HHcy). Studies show that HHcy is a substantial risk factor for cardiovascular, cerebrovascular, and peripheral vascular diseases as well as cognitive impairment and dementia. [129] L-dopa administered to PD patients is metabolized to 3-O-methyl-dopa via methlyation by COMT in peripheral tissues. S-adenosyl-methionine (SAM) provides the methyl group in the reaction and is converted to S-adenosyl-homocysteine (SAH) after donation of the methyl group to L-dopa. Subsequent metabolic reactions metabolize SAH to HHcy, resulting in increased levels of HHcy in plasma.130 It is well recognized that high levels of HHcy can be caused by deficiencies in any one of the three important B vitamins, namely, folate, vitamin B12, and vitamin B6, 129 because HHcy can be catabolized to cysteine by a chain reaction in which vitamin B6 acts as a cofactor, while methionine synthase, an enzyme using vitamin B12 as a cofactor, and 5-methyltetrahydrofolate can also metabolize HHcy to methionine. [130] Reports have shown that PD patients treated with L-dopa exhibit higher HHcy levels in plasma, but a significant reduction in HHcy levels was observed in PD patients supplemented with folate, vitamin B12, and vitamin B6. Therefore, supplementation with these vitamins is important for managing the elevated HHcy levels in PD patients. [129, 131]

Vitamin C, hydrosoluble fiber, and pharmacokinetics

Although findings about the efficacy of the neuroprotective effects of vitamin C were inconclusive, vitamin Cmay improve the efficacy of L-dopa. In a pharmacokinetic study, vitamin C was found to enhance absorption of L-dopa in elderly patients with PD. [132] Another study using water-soluble fiber of Plantago ovata husk showed that treatment of the plant with L-dopa/carbidopa benefits PD patients by relieving constipation and improving the L-dopa profile. [133] These studies suggest that functional foods can help patients via augmentation with drug therapy.



CONCLUSION

The relationship between diet and disease prevention is not a new concept. In fact, the basic theory in Chinese herbal medicine, “medicine and diet share the same origins,” emphasizes that scientific diet strategy may play an undeniable role in human health. One after another, studies have shown the importance of a nutritious diet and active lifestyle as a healthy aging strategy in the prevention of most aging-related diseases, such as cancer, cardiovascular disease, and neurodegenerative diseases. In fact,many populations worldwide have embraced this concept for generations and have incorporated various kinds of nutraceuticals in their diet. Not only should this concept be encouraged as part of daily living to prevent disease, it should also be promoted and applied in a clinical setting.

Nutraceuticals and diet strategies do more than just improve the quality of life for patients.As discussed,when applied in combination with L-dopa drug therapy, B-complex vitamins and vitamin C have positive effects, including reduced side effects and enhanced absorption of L-dopa. These nutraceuticals enhance the effect of contemporary drug therapy and may allow for an attenuated drug dosage, further reducing any dose-dependent side effects. There is much potential in the positive synergistic effects between nutraceuticals and clinical drug therapy. Hence, instead of identifying the neuroprotective effects of nutraceuticals alone, future research should focus on the effects of nutraceuticals in combination with drug therapy. Furthermore, enhanced drug therapy may be developed through design and application of co-drugs linking nutraceuticals and therapeutic drugs, e.g., by linking stilbene compounds to L-dopa or even by linking curcuminoids to L-dopa. This strategy of linking nutraceuticals to drugs may contribute to new drug designs as well as to more well-designed experimental studies and clinical trials.

Nutraceuticals, though attractive and beneficial, are still not the cure for PD. Experimental evidence is too limited to enable the development of effective drugs from nutraceuticals. Well-designed and placebo-controlled human intervention trials are undoubtedly required to confirm experimental findings. Many of the nutraceuticals discussed in this review have been shown to be not only preventative but also therapeutic for PD. Nonetheless, there are still many unknowns, especially with regard to the pharmacokinetics and pharmacodynamics of these nutraceuticals, the effective intake dosage, and the exact therapeutic target, all of which hinders their usage in a clinical setting. High-quality research is needed to promote the entry of more nutraceuticals into therapeutic usage.


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