Nutraceuticals and Their Preventive or Potential Therapeutic Value in Parkinson’s Disease
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.
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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.29
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 Newmark36 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.
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.
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 Study78 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.
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
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.
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]
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.
