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Can We Prevent Parkinson’s and Alzheimer’s Disease?
Correspondence Address:
Parkinson’s disease (PD) and Alzheimer’s (AD) are major progressive neurological disorders, the risk of which increases with advancing age (65 years and over). In familial cases, however, early onset of disease (about 35 years) is observed. In spite of extensive basic and clinical research on PD and AD, no preventive or long-term effective treatment strategies are available. Several studies have indicated that oxidative stress is a major risk factor for the initiation and progression of sporadic PD and AD. Even a-synuclein and b-amyloid fragments that are associated with the PD and AD, respectively, mediate part of their action via oxidative stress. Therefore, reducing oxidative stress appears to be a rational choice for the prevention and reduction in the rate of progression of these neurological disorders. This review provides a brief description of the epidemiology and pathogenesis of PD and AD, and the scientific rationale for the use of multiple antioxidants in the prevention of these neurological diseases.
Parkinson's disease (PD) and Alzheimer's (AD) are major progressive neurological disorders, the risk of which increase with advancing age (65 years and over). Only about 5% of these diseases are due to hereditary factors; the remaining cases are considered to be idiopathic or sporadic. In spite of extensive basic and clinical studies on PD and AD, no preventive or long-term effective treatment strategies are available. The analysis of existing data suggests that increased oxidative stress is a major factor for the initiation and progression of these neurological diseases.[1],[2] We have proposed that oxidative and nitrosylative stress caused by reactive oxygen species (ROS), such as O,-. OH., R, RO2., and H2O2, and reactive nitrogen species (RNS), such as NO., NO2., are major intermediate risk factors for a diverse group of neurotoxins that could initiate and promote neurodegeneration in the brains of PD[3] and AD[4] patients. Therefore any strategy that can reduce the levels of oxidative and nitrosylative stress beginning from a young age may reduce the risk of these neurological diseases during old age. We have further proposed that epigenetic components of neurons (mitochondria, other organelles, membranes, protein modifications) rather than nuclear genes may be the primary targets for the action of neurotoxins, including free radicals in the development of PD and AD.[3],[4] Therefore, improving the functions of these epigenetic components of neurons, and protecting them from further damage by free radicals in patients with early phase disease may help to reduce the rate of progression of symptoms in both PD and AD. The purpose of this review is to discuss recent advances made in the understanding of the aetiology and pathogenesis of PD and AD. It also proposes a scientific rationale for the use of multiple antioxidants at appropriate doses, dose schedules and type of antioxidants to reduce the risk of these diseases in high risk populations and the progression of disease in patients with an early phase disease when no treatment is given.
Results from human epidemiologic studies [3],[4] showed that exposure to excessive amounts of manganese such as observed among manganese miners increases the incidence of a PD-like disease. Increased incidence of PD-like disease is also seen among users of the designer drug, meperidene, which contains 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP), a neurotoxic byproduct formed during the synthesis of this drug. The harmful effects of MPTP and excessive exposure to Mn on DA neurons may in part be mediated through free radicals. Although no particular dietary risk factors for PD have been found, the consumption of nuts, and salad oil (pressed from seeds) have been found to be of protective value. A large community-based study in the Netherlands has reported that vitamin E consumption was significantly lower among patients with PD than among controls. Epidemiologic investigations of AD have also failed to identify environmental, dietary and life-style-related risk factors that could be used for the prevention of this disease. Chronic inflammatory reaction, however, appears to be a major risk factor. This hypothesis is supported by the epidemiologic studies that showed that rheumatoid arthritis patients, who were on high doses of NSAIDs, had a reduced incidence of AD. Accumulation of increased levels of Al and iron, Cu or Zn appears to be also associated with increased risk of AD. Depression symptoms are associated with the increased risk of AD.[5] Contrary to the results published on European and Asian populations, women were not at increased risk for AD.[6]
Parkinson's disease is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by intraneuronal cytoplasmic inclusions called Lewy bodies.[7],[8] The diagnosis of AD is made by postmortem analysis of brains of patients with dementia. The presence of intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein and apolipoprotein E, and extracellular senile (neuritic) plaques containing many proteins, including non-soluble b-amyloid, a-synuclein, ubiquitin, apolipoprotein E, presenilins, and alpha-antichymotrypsin, are considered hallmarks of AD.[9],[10] PD and AD generally are associated with the increased cerebral accumulation of a-synuclein and Ab, respectively. However, some patients have clinical and pathological features of both diseases, suggesting that both a-synuclein and APP may be involved in these diseases.[11]
The brain utilizes about 25% of respired oxygen even though it represents only 5% of the body weight. Free radicals are generated during the normal intake of oxygen, during infection, and during normal oxidative metabolism of certain substrates. During normal aerobic respiration, the mitochondria of one rat nerve cell will process about 10 [12] oxygen molecules and reduce them to water. During this process, superoxide anion, hydrogen peroxide and hydroxyl are produced. In addition, partially reduced oxygen, which represents about 2% of consumed oxygen, leaks out from the mitochondria and generates about 20 billion molecules of O2-• and H2O2 per cell per day.[12] During bacterial or viral infection, phagocytic cells generate high levels of nitric oxide (NO), O2-•, and H2O2 in order to kill infective agents; however, these radicals can also damage normal cells.[12] During degradation of fatty acids and other molecules by peroxisomes, H2O2 is produced as a byproduct. During oxidative metabolism of ingested toxins, free radicals are also generated. Some brain enzymes such as monoamine oxidase (MAO), tyrosine hydroxylase, and L-amino acid oxidase produce H2O2 as a normal byproduct of their activity. Furthermore, auto-oxidation of ascorbate and catecholamines generates H2O2. Oxidative stress can also be generated by Ca2+-mediated activation of glutamate receptors. The Ca2+-dependent activation of phospholipase A2 by N-methyl-D-aspartate (NMDA) releases arachidonic acid, which then liberates O2-• during the biosynthesis of eicosanoid.[13] Another radical, NO, is formed by nitric oxide synthase stimulated by Ca2+. NO can react with O2-• to form peroxynitrite anions that can form OH•, the highly reactive hydroxyl radical. Some enzymes such as xanthine oxidase and flavoprotein oxidase (e.g. aldehyde oxidase) also form superoxide anions during metabolism of their respective substrates. Oxidation of hydroquinone and thiol, and synthesis of uric acid from purines form superoxide anions. Several different types of radicals are constantly formed in the brain. Their levels can be increased by enhanced turnover of catecholamines, increased levels of free iron, impaired mitochondrial function, decreased glutathione levels, decreased levels of catalase, glutathione peroxidase or superoxide dismutase. Cigarette smoking increases the level of NO by about 1000 ppm and depletes antioxidant levels.[14],[15] Dietary phenolic compounds such as chlorogenic and caffeic acid when oxidized act as free radicals. These studies suggest that the brain generates high levels of ROS and RNS every day. Paradoxically, the brain is least prepared to handle this excessive load of free radicals. It has low levels of both antioxidant enzyme systems and dietary antioxidants. These inherent biological features make the brain very vulnerable to oxidative and nitrosylative stress. Despite this, the risk of idiopathic PD or AD becomes significant only after the age of 65 or more. This is due to the fact that neurons exhibit a high degree of plasticity in maintaining normal brain functions. The fact that clinical symptoms PD and AD appear only when a significant number of neurons are lost, supports the value of plasticity of the neurons in maintaining normal brain function. Supplementation with antioxidants vitamin A, C, and E, natural b-carotene, co-enzyme Q10, a-lipoic acid, N-acetyl-cysteine and NADH may reduce the rate of loss of neurons.
The normal brain has the highest concentration of unsaturated fatty acids compared to other organs and these fatty acids are very susceptible to lipid peroxidation.[16] The substantia nigra (SN) is the primary area of the brain that undergoes degeneration in PD. Autopsy samples of SN from PD brains revealed increased oxidant levels and decreased antioxidant levels. For example, increased levels of free iron were demonstrated in autopsy samples[17] as well as in brains of living PD patients by iron-mediated contrast magnetic resonance imaging (MRI).[18] SN samples from PD brains have reduced levels of antioxidant enzymes,[19],[20] and reduced levels of antioxidants.[21] The above changes increase the balance in favor of a pro-oxidant environment, which can increase oxidative damage. Indeed, evidence of oxidative damage in the autopsy samples of brain of PD has been observed.[22],[23],[24]
Point mutations in the a-synuclein gene which codes for a presynaptic nerve terminal protein are associated with familial PD.[25] Immortalized DA neurons expressing mutated a-synuclein gene showed increased sensitivity to 6-hydroxydopamine.[26] In addition, it has been reported that a-synuclein-induced apoptosis may be due to increased oxidative damage.[27],[28],[29] In another study, it has been shown that in some cases nitrated a-synuclein is present in inclusion bodies of AD and PD.[30] This suggests that a-synuclein increases oxidative damage and nitrosylative damage that may also play a crucial role in neurodegeneration. A study has reported that mutations in the Parkin gene are associated with autosomal recessive juvenile parkinsonism (AR-JP).[31] It is unknown whether the mutated Parkin gene mediates its effect on neurons via increasing oxidative stress.
Increased oxidative stress has been implicated in the loss of neurons associated with AD.[32] Mitochondria may be one of the most sensitive primary targets that increase oxidative stress in adult neurons.[33],[34] This may be due to the fact that mitochondrial DNA (mtDNA) does not encode for any repair enzymes, and, unlike nuclear DNA, it is not shielded by protective histones. In addition, mtDNA is in close proximity to the site where free radicals are generated during oxidative phosphorylation. Indeed, an increased frequency of mutations in mtDNA has been found in autopsy samples of AD brains,[33] and thus mitochondrial defects may be involved in the pathogenesis of AD.[34],[35] A defect in energy production may also increase the sensitivity of neurons to excitatory amino acids.[36] Impaired mitochondria increased generation of potentially amyloidogenic derivatives.[37] Excess of free Zn is found in the autopsied brain of AD and increased free Zn can impair mitochondrial function.[38] It is interesting to note that in AD patients who carry ApoE4 allele of ApoE gene, the clinical Dementia Rating (CDR) correlated better with KGDHC activity than with densities of neuritic plaques and NTFs; however, in patients without ApoE4, the CDR correlated better with plaques and NTFs than with KGDHC activity.[39] This suggests that mitochondrial dysfunction may be more important for the development of AD in patients who carry ApoE4 allele than in those who do not. Increased oxidative stress may enhance intracellular accumulation of Ab in neurons.[40] In addition, studies show that membrane containing oxidatively damaged phospholipids accumulated Ab faster than membrane containing only normal saturated phospholipids.[41] It has been proposed that one of the mechanisms of action in Ab neurotoxicity is mediated by free radicals.[42] This was confirmed by a series of studies on substitutions of amino acid,[43] and also by the fact that vitamin E protects neuronal cells in culture against Ab-induced toxicity.[44] Experiments on a transgenic mouse model of AD support the concept that Ab-induced neurotoxicity is mediated by oxidative stress. For example, it has been reported that Cu/Zn superoxide dismutase (SOD), and hemoxygenase-1 (HO-1), markers of oxidative stress, were elevated in aged transgenic mice.[45] Other evidence of increased oxidative stress in AD include the following: (a) the serum levels of vitamins A, E and b-carotene were lower in patients with AD (who were well nourished) than in control patients;[46] (b) higher expression of heme oxygenase is found in the autopsy samples of brains of AD patients;[47] (c) increased consumption of oxygen is found in AD patients;[48] (d) increased activity of glucose-6-phosphate dehydrogenase is found in the autopsy samples of AD brain;[49] and (e) activation of calcium-dependent neural proteinase (calpain) is found in the autopsy samples of AD brains which may trigger events leading to the formation of free radicals;[50] (f) homogenates of frontal cortex from the autopsy samples of AD brains revealed a 22% higher production of free radicals and, in the presence of iron, a 50% higher production of free radicals than those of age-matched normal controls;[51] (g) besides oxidative stress, nitrosylative stress, which is primarily mediated by peroxynitrites, can potentially exacerbate the pathogenesis of AD;[52] (h) increased neuronal nitric oxide synthase (nNOS) expression in reactive astrocytes correlated with apoptosis in hippocampal neurons of AD brains;[53] (i) glutamine synthetase, a highly sensitive enzyme to oxidative stress, showed decreased activity in the autopsy samples of AD brains;[54] (j) the level of glutathione transferase is decreased in ventricular CSF and in the autopsy samples of AD brains compared to brains from age- matched controls;[55] and (f) increased levels of oxidized proteins are found in the blood of both AD patients and their relatives when compared with non-AD control.[54] Evidence for oxidative and nitrosylative damage at autopsy in the brains of AD patients have also been reported.[55],[56]
In some familial AD, mutations (about seven) in the APP gene have been reported, all of which increase the production of b-amyloid;[57] however, this accounts for less than 1 % of all familial AD. Mutations (about fifty) in presenilin-I gene have been found in about 50% of familial AD,[57] whereas mutations in presenilin-II have been observed in less than 1% of familial AD.[58] The interaction between APP and presenilin I or presenilin II may increase production and release of b-amyloid.[59] It should be noted that in spite of mutations in APP and presenilin genes, a minimum of about 30 years is needed for the development of familial AD. This suggests that the products of mutated genes by themselves are not toxic. It is possible that cells expressing these gene mutations may become more sensitive to neurotoxins including oxidative and nitrosylative stress. Indeed, we have shown that the expression of high levels of wild type APP in differentiated neuroblastoma cells makes these cells more sensitive to neurotoxins such as PGE2, PGA1, oxidative and nitrosylative stress.[60]
No genetic defects in idiopathic PD have been demonstrated as yet. Polymorphism in certain genes such as those that code for dopamine-transporter protein,[61] alpha-1-antichymotrypsin,[62] monoamine oxidase B[63] and cytochrome P4501A1 (CYP1A1)[64] have been associated with increased risk of idiopathic PD. Polymorphism in DA neurons could lead to increased accumulation of neurotoxins in these cells. Since polymorphism in these genes was measured in peripheral cells, it is difficult to suggest that it also occurs in DA neurons. In addition, there is no direct evidence that polymorphic genes are either neurotoxic or increase the sensitivity of DA neurons to neurotoxic agents.
There is no solid evidence for nuclear gene defects that can increase the risk of idiopathic AD, although varying degrees of association between certain gene defects and onset of this disease exist. Several studies have suggested that persons who are homozygous for the apolipoprotein E (APOE), e4 allele, develop AD 10-20 years earlier than those who have e2 or e3 alleles.[65] Even persons who are heterozygous for e4 allele develop AD 5-10 years earlier than those who have e2 or e3 alleles.[66] About 40 % of idiopathic AD is associated with the presence of e4 allele, and it is present in the senile plaque.[66] These data suggest that the presence of e4 allele could be an important risk factor for AD. However, it was shown that this allele is neither essential nor specific for the development of AD.[66] Thus, the role of this APOE allele in neurodegeneration is uncertain. Mutation in the ubiquitin gene[67] and down-regulation of presenilin II[68],[69] have been observed in the autopsy samples of AD brains.
We have proposed a hypothesis that epigenetic components (mitochondria, proteasomes, post-translational modification of proteins) rather than nuclear genes are the primary targets for the action of diverse groups of neurotoxins in idiopathic PD and AD.[3],[4] For example, mitochondrial dysfunction is associated with both PD and AD; therefore; it may represent an early event in the pathogenesis of these neurological disorders.[3],[4] Even in cases of familial AD, the products of mutated genes by themselves are not neurotoxic, rather they affect epigenetic components such as post-translational modification of proteins (increased processing of APP to Ab40 and Ab42) that could increase oxidative stress and/or make neurons more sensitive to oxidative stress. We also suggest that the shift in processing of APP to Ab42 in AD brain is an example of post-translational modification of protein caused by certain neurotoxins. Proteasome represents another example of an epigenetic component and it regulates certain transcriptional factors by splicing inactive peptide fragments on to active ones, and protein levels by degrading ubiquitin-conjugated abnormal proteins. Therefore, inhibition of proteasome in neurons can initiate and promote neurodegeneration. Indeed, the role of proteasome inhibition has been proposed for the degeneration of neurons in AD brains,[70],[71] and Ab is one of the factors that inhibits proteasome activity.[72] A defect in ubiquitin conjugate enzymes[73] or a mutation in ubiquitin (Ub) could also impair removal of unwanted proteins via proteasome. We have shown that inhibition of proteasome by lactacystin causes rapid degeneration of cAMP-induced differentiated neuroblastoma cells in culture.[74] Furthermore, we have suggested[4] that increased accumulation of ubiquitin[10],[75] and hyperphosphorylated tau protein[76] in AD brains is a reflection of inhibition of proteasome activity. Cholesterol levels also represent one of the epigenetic components of neurons. Epidemiologic studies showed that hypercholesterolemia may be a risk factor in the development of AD,[77],[78],[79],[80] and that lovastatin, an inhibitor of HMG CoA reductase, reduces the risk of AD in hypercholesterolemic patients.[81] The role of cholesterol was confirmed in the transgenic animal model of AD in which high dietary cholesterol increases Ab accumulation and thereby accelerates AD-related pathology in animals.[82] An accumulation of Ab can be reversed by removing cholesterol from the rabbit's diet.[82] Inhibitors of HMG CoA reductase decrease the production of Ab in rabbit and in fetal rat hippocampal neurons in culture.[83] These results suggest that some of the effects of cholesterol are primarily mediated via Ab rather than via poor circulation due to thickening of the arteries. Statins with a closed- ring structure (lovastatin, simvastatin, mevastatin) are metabolized in vivo to an open-ring structure which then inhibits HMG CoA reductase activity. Recently, we have demonstrated that mevastatin with a closed-ring structure caused rapid degeneration of differentiated neuroblastoma (NB) cells in culture, whereas, pravastatin with an open-ring structure did not.[84] Mevastatin-induced degeneration of differentiated NB cells may be related to inhibition of proteasome activity.[84] These studies suggest that lowering cholesterol levels could reduce the risk of AD, whereas the presence of increased amounts of unmetabolized statins with a closed -ring structure could increase the risk of AD. Another study has shown that cholesterol-fed rabbits placed on distilled water have a 28% reduction in the level of b-amyloid in comparison to those on tap water.[85]
In order to investigate the effect of antioxidants in an animal model of Parkinsonism, it is essential to study whether antioxidant supplementation can increase brain levels of antioxidants. It has been reported that dietary supplementation with dl-alpha tocopherol (1000 I.U./day) for 4 months increased rat brain levels of vitamin E by about 1.4 fold.[86] The brain and cerebrospinal fluid levels of vitamin E also increased by 2-fold in dogs treated with vitamin E supplements for 2 years.[87] These studies suggested that supplementation with vitamin E could be of protective value in an animal model of PD. Indeed, supplementation with vitamin E and vitamin C88 protected rats against 6-hydroxydopamine-induced striatal damage (rat model of PD). In vitro experiments reveal that vitamin E protects neurons against 6-hydroxydopamine which is known to mediate its action in part by free radicals.[89] Additional studies on the efficacy of multiple antioxidants in reducing the symptoms of PD in animal models are needed.
The effect of antioxidants in animal model of AD has not been investigated. In vitro studies show that vitamin E can protect neurons against neurotoxins such as glutamate[90] which is known to mediate its action in part by free radicals. Vitamin E also protects rats against aggregated Ab-induced behavioral impairments.[91] Lysosomes play a key role in preventing the formation of amyloid deposits and senile plaques, and vitamin C improves lysosomal functions of human brain astrocytes[92] and thereby preserves cellular function. Additional studies on the efficacy of multiple antioxidants in reducing the symptoms of AD in animal models are needed.
In a preliminary study, supplementation with vitamin E (3,000 I.U./day) and vitamin C (3,000 mg/day) increased the time interval for requiring L-dopa therapy by about 2-4 years in 75% of patients when compared to historical controls; however, 16% of patients on vitamin therapy did not require L-dopa therapy at the time of writing the manuscript (about 8 years).[93] In contrast to the above study, a large clinical, double-blind, and placebo-controlled study involving 800 patients in the early stages of untreated PD was initiated to evaluate the efficacy of alpha-tocopherol and deprenyl on the rate of progression of PD.[94] This study was referred to as Deprenyl and Tocopherol Antioxidant Therapy of Parkinsonism (DATATOP). The major endpoint of this study was the time interval between initiation of experimental treatment and need for L-dopa treatment. Synthetic dl-alpha-tocopherol at a daily dose of 2,000 I.U. was given orally. This study failed to show any significant improvements based on the proposed endpoint.[94] This clinical study failed to consider the consequence of metabolism of high dose vitamin E, multifactorial nature of the disease, reduced levels of other antioxidants such as glutathione, and the value of NADH that increases the level of dopamine.
A controlled clinical trial with dl-a tocopherol (synthetic form; 2,000 IU/day) in patients with moderately severe impairment from AD showed some beneficial effects with respect to rate of deterioration of cognitive function[95] Although this important clinical study supports the role of free radicals in the progression of AD, the use of a single antioxidant, vitamin E, and the administration regime (once a day) may not have been optimal for quenching all the various types of free radicals that are produced in the brain. For example, It has been reported that rat organs preferentially absorb the natural form of vitamin E;[96] therefore, the use of synthetic vitamin E in any clinical study may not be useful. In addition, the a-tocopherol form of vitamin E may not cross the blood-brain barrier as efficiently as d-a-tocopheryl succinate (a-TS), since a-TS is more soluble in ethanol, and enters the mammalian cell more readily than a-tocopherol.[97] Therefore the use of a-TS may be beneficial. In addition, the use of a single antioxidant may not be prudent for long-term therapy, because very high doses of a single antioxidant that may be needed to produce a beneficial effect in AD patients, and such high doses can cause a clotting defect. In the same trial as above, selegiline (10 mg a day), a monoamine oxidase inhibitor, or dl-a tocopherol slowed the progression of disease in patients with moderately severe impairments from AD.[95] It was interesting to note that there was no significant difference in the effect between the groups receiving a combination of dl-a-alpha tocopherol and selegiline and those receiving treatment with the individual agents.[95] In our opinion, this was expected because both selegiline and vitamin E reduce the levels of ROS, although by different mechanisms. For example, vitamin E protects neurons by destroying formed free radicals (“quenching”), whereas selegiline protects neurons by preventing the formation of ROS through inhibiting oxidative metabolism of catecholamines.
Prevention strategies can be developed if the risk and protective factors for PD and AD are known. Based on current knowledge of risk and protective factors, we propose prevention strategies for those who have no clinical symptoms of PD or AD, and those who are at high risk for developing these neurological disorders. This involves a diet rich in antioxidants and moderate supplements with multiple antioxidants right from childhood that can maintain brain antioxidants at levels that are higher than normally provided by the nature.
The biological rationale for using multiple antioxidants is described below. Beta-carotene (BC) is more effective in quenching oxygen radicals than most other antioxidants.[98] BC can produce certain effects that cannot be produced by its metabolite vitamin A, and vice versa.[99] The gradient of atmospheric (oxygen) pressure varies within the tissue. Some antioxidants such as vitamin E are more effective quenchers of free radicals in reduced oxygen pressure, whereas BC and vitamin A are more effective at higher atmospheric pressure.[100] Vitamin C is necessary to protect cellular components in aqueous environments, whereas carotenoids, vitamins A and E protect cellular components in non-aqueous environments. In addition, vitamin C is necessary for the activity of tyrosine hydroxylase, which is the rate-limiting enzyme in the synthesis of catecholamines. Vitamin C also plays an important role in maintaining cellular levels of vitamin E by recycling the vitamin E radical.[101] Also, oxidative damage produced by vitamin C (oxidized adenine nucleotides) could be protected by vitamin E. We have reported that oral ingestion of a-TS (800 I.U./day) in humans increased plasma levels of not only a-tocopherol, but also a-TS, suggesting that a-TS can be absorbed from the intestinal tract before hydrolysis to a-tocopherol.[97] Levels of reduced glutathione decrease in PD.[102] Glutathione is effective in catabolizing H2O2 and anions. However, oral supplementation with glutathione failed to significantly increase plasma levels of glutathione in human subjects[103] suggesting that this tripeptide is completely hydrolyzed in the G.I. tract. N-acetylcysteine and a-lipoic acid that increase glutathione levels would be useful. Since mitochondrial dysfunction is associated with PD, and since coenzyme Q10 and nicotinamide adenine dinucleotide (reduced form, NADH) are needed for generation of ATP by mitochondria, it is essential to use these antioxidants among the high-risk populations. A study has shown[104] that ubiquinol (coenzyme Q10) scavenges peroxy radicals faster than a-tocopherol, but it is rapidly oxidized to give hydroperoxy radicals and/or superoxide. Therefore, it is a weaker antioxidant than a-tocopherol. However, ubiquinol, like vitamin C, can regenerate vitamin E in a redox cycle.[105] Coenzyme Q10 administration improves clinical symptoms in patients with mitochondrial encephalomyopathies.[106] NADH administration (1.4 mg/Kg) has been useful in 415 PD patients.[107] In addition to acting as an antioxidant, it can stimulate the production of L-dopa in vivo[108] and dopamine in PC-12 cells, a dopaminergic cell line as well as ATP.[109] Selenium is a co-factor of glutathione peroxidase; therefore, selenium supplementation is essential.
The levels of risk and protective factors in the brain may very from one individual to another, depending upon the age, exposure to neurotoxins including free radicals, pharmacokinetics and consumption of diets or supplements rich in antioxidants. Therefore, we have divided recommendations based on age and population at risk for PD and AD. These recommendations have been summarized in [Table - 1].
Early stage PD is referred to as a condition where no L-dopa therapy is required. Therefore, any significant extension of this time interval would be an important contribution to the management of PD. Recommended antioxidants have been summarized in [Table - 2].
Reactive oxygen species and reactive nitrogen species play an important role in the progression of neurodegeneration in AD. Therefore, multiple antioxidant supplements as an adjunct to standard therapy in the treatment of AD would be more useful than the individual agents alone. NADH administration (10 mg/day before meal) has been beneficial in a pilot study of 17 AD patients.[110] Selenium is a co-factor of glutathione peroxidase, and Se-glutathione peroxidase also acts as an antioxidant. Therefore, selenium supplementation together with other antioxidants is also essential. In addition to antioxidants, vitamin B-12 may have some role in the treatment of AD. In most studies the serum levels of vitamin B-12 in AD patients were significantly lower than controls, and this may partly contribute to degeneration of neurons.[111] Indeed, vitamin B-12 supplementation increased choline acetyltransferase activity in cholinergic neurons in cats[112] and improved cognitive functions in AD patients.[113] Therefore, the inclusion of vitamin B-12 in multiple antioxidant preparations may be useful. Multiple antioxidants recommended for early phase AD patients are described [Table - 2].
Even though, there is no direct link between the diet and lifestyle related factors and the risk of PD and AD or progression of these diseases, it is always useful to include a balanced diet that contains low fat and plenty of fruits and vegetables rich in antioxidants. Among fruits, blueberries and raspberries are particularly important because of their protective role against oxidative injuries in brain. Lifestyle recommendations include daily moderate exercise, reduced stress and no tobacco smoking, avoiding exposure to pesticides, and avoiding the intake of iron, Cu, Mn and Zn through supplements. These recommendations are not specific to PD or AD. They are for general optimal health.
This study was supported by the US Public Health Service Grant AG 18285
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