Can We Prevent Parkinson’s and Alzheimer’s Disease?
Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine,
N P Kedar
Campus Box C-278, UCHSC, 4200 E. 9th Ave., Denver, Colorado, 80262
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.
|How to cite this article:|
Kedar N P. Can We Prevent Parkinson’s and Alzheimer’s Disease?
.J Postgrad Med 2003;49:236-245
|How to cite this URL:|
Kedar N P. Can We Prevent Parkinson’s and Alzheimer’s Disease?
. J Postgrad Med [serial online] 2003 [cited 2022 Aug 17 ];49:236-245
Available from: https://www.jpgmonline.com/text.asp?2003/49/3/236/1140
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., 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 and AD 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., 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 , 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. Contrary to the results published on European and Asian populations, women were not at increased risk for AD.
Pathogenesis of PD and AD
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., 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., 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.
Sources of oxidative stress in normal brain
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  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. 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. 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. 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., 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.
Evidence for the involvement of oxidative and nitrosylative stress in idiopathic PD brain
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. 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 as well as in brains of living PD patients by iron-mediated contrast magnetic resonance imaging (MRI). SN samples from PD brains have reduced levels of antioxidant enzymes,, and reduced levels of antioxidants. 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.,,
Evidence for the involvement of oxidative stress in familial PD brain
Point mutations in the a-synuclein gene which codes for a presynaptic nerve terminal protein are associated with familial PD. Immortalized DA neurons expressing mutated a-synuclein gene showed increased sensitivity to 6-hydroxydopamine. In addition, it has been reported that a-synuclein-induced apoptosis may be due to increased oxidative damage.,, In another study, it has been shown that in some cases nitrated a-synuclein is present in inclusion bodies of AD and PD. 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). It is unknown whether the mutated Parkin gene mediates its effect on neurons via increasing oxidative stress.
Evidence for the involvement of oxidative and nitrosylative stress in idiopathic AD brain
Increased oxidative stress has been implicated in the loss of neurons associated with AD. Mitochondria may be one of the most sensitive primary targets that increase oxidative stress in adult neurons., 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, and thus mitochondrial defects may be involved in the pathogenesis of AD., A defect in energy production may also increase the sensitivity of neurons to excitatory amino acids. Impaired mitochondria increased generation of potentially amyloidogenic derivatives. Excess of free Zn is found in the autopsied brain of AD and increased free Zn can impair mitochondrial function. 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. 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. In addition, studies show that membrane containing oxidatively damaged phospholipids accumulated Ab faster than membrane containing only normal saturated phospholipids. It has been proposed that one of the mechanisms of action in Ab neurotoxicity is mediated by free radicals. This was confirmed by a series of studies on substitutions of amino acid, and also by the fact that vitamin E protects neuronal cells in culture against Ab-induced toxicity. 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.
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; (b) higher expression of heme oxygenase is found in the autopsy samples of brains of AD patients; (c) increased consumption of oxygen is found in AD patients; (d) increased activity of glucose-6-phosphate dehydrogenase is found in the autopsy samples of AD brain; 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; (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; (g) besides oxidative stress, nitrosylative stress, which is primarily mediated by peroxynitrites, can potentially exacerbate the pathogenesis of AD; (h) increased neuronal nitric oxide synthase (nNOS) expression in reactive astrocytes correlated with apoptosis in hippocampal neurons of AD brains; (i) glutamine synthetase, a highly sensitive enzyme to oxidative stress, showed decreased activity in the autopsy samples of AD brains; (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; 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. Evidence for oxidative and nitrosylative damage at autopsy in the brains of AD patients have also been reported.,
Evidence for the involvement of oxidative stress in familial AD brain
In some familial AD, mutations (about seven) in the APP gene have been reported, all of which increase the production of b-amyloid; 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, whereas mutations in presenilin-II have been observed in less than 1% of familial AD. The interaction between APP and presenilin I or presenilin II may increase production and release of b-amyloid. 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.
Involvement of nuclear genes in idiopathic PD
No genetic defects in idiopathic PD have been demonstrated as yet. Polymorphism in certain genes such as those that code for dopamine-transporter protein, alpha-1-antichymotrypsin, monoamine oxidase B and cytochrome P4501A1 (CYP1A1) 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.
Involvement of nuclear genes in idiopathic AD
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. Even persons who are heterozygous for e4 allele develop AD 5-10 years earlier than those who have e2 or e3 alleles. About 40 % of idiopathic AD is associated with the presence of e4 allele, and it is present in the senile plaque. 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. Thus, the role of this APOE allele in neurodegeneration is uncertain. Mutation in the ubiquitin gene and down-regulation of presenilin II, have been observed in the autopsy samples of AD brains.
Epigenetic components of neurons are primary targets of actions of a diverse group of neurotoxins in idiopathic PD and AD
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., 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.,
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,, and Ab is one of the factors that inhibits proteasome activity. A defect in ubiquitin conjugate enzymes 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. Furthermore, we have suggested that increased accumulation of ubiquitin, and hyperphosphorylated tau protein 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,,,, and that lovastatin, an inhibitor of HMG CoA reductase, reduces the risk of AD in hypercholesterolemic patients. 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. An accumulation of Ab can be reversed by removing cholesterol from the rabbit's diet. Inhibitors of HMG CoA reductase decrease the production of Ab in rabbit and in fetal rat hippocampal neurons in culture. 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. Mevastatin-induced degeneration of differentiated NB cells may be related to inhibition of proteasome activity. 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.
Laboratory studies with antioxidants in PD
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. The brain and cerebrospinal fluid levels of vitamin E also increased by 2-fold in dogs treated with vitamin E supplements for 2 years. 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. Additional studies on the efficacy of multiple antioxidants in reducing the symptoms of PD in animal models are needed.
Laboratory studies with antioxidants in AD
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 which is known to mediate its action in part by free radicals. Vitamin E also protects rats against aggregated Ab-induced behavioral impairments. 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 and thereby preserves cellular function. Additional studies on the efficacy of multiple antioxidants in reducing the symptoms of AD in animal models are needed.
Clinical studies with antioxidants in PD
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). 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. 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. 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.
Clinical studies with antioxidants in AD
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 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; 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. 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. 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. 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 for PD and AD
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.
Rationale for using multiple antioxidants for PD and AD prevention
The biological rationale for using multiple antioxidants is described below.
Beta-carotene (BC) is more effective in quenching oxygen radicals than most other antioxidants. BC can produce certain effects that cannot be produced by its metabolite vitamin A, and vice versa. 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. 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. 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. Levels of reduced glutathione decrease in PD. Glutathione is effective in catabolizing H2O2 and anions. However, oral supplementation with glutathione failed to significantly increase plasma levels of glutathione in human subjects 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 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. Coenzyme Q10 administration improves clinical symptoms in patients with mitochondrial encephalomyopathies. NADH administration (1.4 mg/Kg) has been useful in 415 PD patients. In addition to acting as an antioxidant, it can stimulate the production of L-dopa in vivo and dopamine in PC-12 cells, a dopaminergic cell line as well as ATP. Selenium is a co-factor of glutathione peroxidase; therefore, selenium supplementation is essential.
Recommended multiple antioxidants for prevention
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].
Recommended multiple antioxidants for early phase PD
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].
Recommended multiple antioxidants in early phase AD patients
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. 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. Indeed, vitamin B-12 supplementation increased choline acetyltransferase activity in cholinergic neurons in cats and improved cognitive functions in AD patients. 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].
Diet and lifestyle recommendations
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
|1||Olanow CW, Youdim MB. Neurodegeneration and neuroprotection in Parkinson's disease. New York: Academic Press; 1996. |
|2||Schapira AH. Pathogenesis of Parkinson's disease. Baillieres Clin Neurol 1997;6:15-36|
|3||Prasad KN, Cole WC, Kumar B. Multiple antioxidants in the prevention and treatment of Parkinson's disease. J Am Coll Nutr 1999;18:413-23|
|4||Prasad KN, Cole WC, Prasad KC. Risk factors for Alzheimer's disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. J Am Coll Nutr 2002;21:506-22|
|5||Green RC, Cupples LA, Kurz A, Auerbach S, Go R, Sadovnick D, et al. Depression as a risk factor for Alzheimer disease. Arch Neurol 2003;60:753-9|
|6||Edland SD, Rocca WA, Petersen RC, Cha RH, Kokmen E. Dementia and Alzheimer disease incidence rates do not vary by sex in Rochester. Minn Arch Neurol 2002;59:1589-93.|
|7||Lang AE, Lozano AM. Parkinson's disease. First of two parts. N Engl J Med 1998;339:1044-53.|
|8||Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med 1998;339:1130-43.|
|9||Selkoe DJ. Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease. Annu Rev Cell Biol 1994;10:373-403.|
|10||Kudo T, Iqbal K, Ravid R, Swaab DF, Grundke-Iqbal I. Alzheimer disease: correlation of cerebro-spinal fluid and brain ubiquitin levels. Brain Res 1994;639:1-7.|
|11||Suh YH, Checler F. Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol Rev 2002;54:469-525.|
|12||Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 1993;90:7915-22.|
|13||Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J. NMDA-dependent superoxide production and neurotoxicity. Nature 1993;364:535-7.|
|14||Kiyosawa H, Suko M, Okudaira H, Murata K, Miyamoto T, Chung MH, et al. Cigarette smoking induces formation of 8-hydroxydeoxyguanosine, one of the oxidative DNA damages in human peripheral leukocytes. Free Radic Res Commun 1990;11:23-7.|
|15||Reznick AZ, Cross CE, Hu ML, Suzuki YJ, Khwaja S, Safadi A, et al. Modification of plasma proteins by cigarette smoke as measured by protein carbonyl formation. Biochem J 1992;286:607-11.|
|16||Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J Neurochem 1989;52:381-9.|
|17||Dexter DT, Wells FR, Agid F, Agid Y, Lees AJ, Jenner P, et al. Increased nigral iron content in postmortem parkinsonian brain. Lancet 1987;2:1219-20.|
|18||Gorell JM, Ordidge RJ, Brown GG, Deniau JC, Buderer NM, Helpern JA. Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease. Neurology 1995;45:1138-43.|
|19||Ambani LM, Van Woert MH, Murphy S. Brain peroxidase and catalase in Parkinson disease. Arch Neurol 1975;32:114-8.|
|20||Kish SJ, Morito C, Hornykiewicz O. Glutathione peroxidase activity in Parkinson's disease brain. Neurosci Lett 1985;58:343-6.|
|21||Sofic E, Lange KW, Jellinger K, Riederer P. Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease. Neurosci Lett 1992;142:128-30.|
|22||Dexter DT, Holley AE, Flitter WD, Slater TF, Wells FR, Daniel SE, et al. Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Mov Disord 1994;9:92-7.|
|23||Sanchez-Ramos J, Overvik E, Ames B. A marker of oxyradical-mediated DNA damage (8-hydroxy-2'-deoxyguanosine) is increased in nigro-striatum of Parkinson's disease brain. Neurodegeneration 1994;3:197-204.|
|24||Ebadi M, Srinivasan SK, Baxi MD. Oxidative stress and antioxidant therapy in Parkinson's disease. Prog Neurobiol 1996;48:1-19.|
|25||Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045-7.|
|26||Zhou W, Hurlbert MS, Schaack J, Prasad KN, Freed CR. Overexpression of human alpha-synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells. Brain Res 2000;866:33-43.|
|27||Tabner BJ, Turnbull S, El-Agnaf OM, Allsop D. Formation of hydrogen peroxide and hydroxyl radicals from A(beta) and alpha-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease. Free Radic Biol Med 2002;32:1076-83.|
|28||Zhou W, Schaack J, Zawada WM, Freed CR. Oveexpression of human a-synuclein causes dopamine neuron death in primary human mesencephalic culture. Brain Res 2002;926:42-50.|
|29||Zhou W, Hurlbert MS, Schaack J, Prasad KN, Freed CR. Overexpression of human alpha-synuclein causes dopamine neuron death in rat primary culture and immortalized mesecephalon-derived cells. Brain Res 2000;866:33-43.|
|30||Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000;290:985-9.|
|31||Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392:605-8|
|32||Harman D. A hypothesis on the pathogenesis of Alzheimer's disease. Ann N Y Acad Sci 1996;786:152-68|
|33||Shoffner JM, Brown MD, Torroni A, Lott MT, Cabell MF, Mirra SS et al. Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 1993;17:171-84|
|34||Saraiva AA, Borges MM, Madeira MD, Tavares MA, Paula-Barbosa MM. Mitochondrial abnormalities in cortical dendrites from patients with Alzheimer's disease. J Submicrosc Cytol 1985;17:459-64|
|35||Bowling AC, Beal MF. Bioenergetic and oxidative stress in neurodegenerative diseases. Life Sci 1995;56:1151-71|
|36||Mattson MP. Calcium and neuronal injury in Alzheimer's disease. Contributions of beta-amyloid precursor protein mismetabolism, free radicals, and metabolic compromise. Ann N Y Acad Sci 1994;747:50-76.|
|37||Gabuzda D, Busciglio J, Chen LB, Matsudaira P, Yankner BA. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 1994;269:13623-8.|
|38||Brown AM, Kristal BS, Effron MS, Shestopalov AI, Ullucci PA, Sheu KF, et al. Zn2+ inhibits alpha-ketoglutarate-stimulated mitochondrial respiration and the isolated alpha-ketoglutarate dehydrogenase complex. J Biol Chem 2000;275:13441-7.|
|39||Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q, Lesser M, et al. Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. Ann Neurol 2000;48:297-303.|
|40||Misonou H, Morishima-Kawashima M, Ihara Y. Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry 2000;39:6951-9.|
|41||Koppaka V, Axelsen PH. Accelerated accumulation of amyloid beta proteins on oxidatively damaged lipid membranes. Biochemistry 2000;39:10011-6.|
|42||Schubert D, Behl C, Lesley R, Brack A, Dargusch R, Sagara Y, et al. Amyloid peptides are toxic via a common oxidative mechanism. Proc Natl Acad Sci USA 1995;92:1989-93.|
|43||Varadarajan S, Yatin S, Kanski J, Jahanshahi F, Butterfield DA. Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress. Brain Res Bull 1999;50:133-41.|
|44||Behl C, Davis J, Cole GM, Schubert D. Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Commun 1992;186:944-50.|
|45||Pappolla MA, Chyan YJ, Omar RA, Hsiao K, Perry G, Smith MA, et al. Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol 1998;152:871-7.|
|46||Zaman Z, Roche S, Fielden P, Frost PG, Niriella DC, Cayley AC. Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease. Age Ageing 1992;21:91-4.|
|47||Smith MA, Kutty RK, Richey PL, Yan SD, Stern D, Chader GJ, et al. Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease. Am J Pathol 1994;145:42-7.|
|48||Sims NR, Bowen DM, Neary D, Davison AN. Metabolic processes in Alzheimer's disease: adenine nucleotide content and production of 14CO2 from [U-14C]glucose in vitro in human neocortex. J Neurochem 1983;41:1329-34.|
|49||Martins RN, Harper CG, Stokes GB, Masters CL. Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer's disease may reflect oxidative stress. J Neurochem 1986;46:1042-5.|
|50||Saito K, Elce JS, Hamos JE, Nixon RA. Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci USA 1993;90:2628-32.|
|51||Zhou Y, Richardson JS, Mombourquette MJ, Weil JA. Free radical formation in autopsy samples of Alzheimer and control cortex. Neurosci Lett 1995;195:89-92.|
|52||Koppal T. Peroxynitrite-mediated damage to brain membrane alterations in Alzheimer's disease (AD). Soc Neurosci 1998;24:1217a.|
|53||Simic G, Lucassen PJ, Krsnik Z, Kruslin B, Kostovic I, Winblad B, et al. nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer's disease. Exp Neurol 2000;165:12-26.|
|54||Conrad CC, Marshall PL, Talent JM, Malakowsky CA, Choi J, Gracy RW. Oxidized proteins in Alzheimer's plasma. Biochem Biophys Res Commun 2000;275:678-81.|
|55||McIntosh LJ, Trush MA, Troncoso JC. Increased susceptibility of Alzheimer's disease temporal cortex to oxygen free radical-mediated processes. Free Radic Biol Med 1997;23:183-90.|
|56||Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci 1997;17:2653-7.|
|57||Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995;375:754-60.|
|58||Busciglio J, Hartmann H, Lorenzo A, Wong C, Baumann K, Sommer B, et al. Neuronal localization of presenilin-1 and association with amyloid plaques and neurofibrillary tangles in Alzheimer's disease. J Neurosci 1997;17:5101-7.|
|59||Dewji NN, Singer SJ. Genetic clues to Alzheimer's disease. Science 1996;271:159-60.|
|60||Hanson AJ, Prasad JE, Nahreini P, Andreatta C, Kumar B, Yan XD, et al. The overexpression of amyloid precursor protein is associated with degeneration, decreased viability, and increased damage caused by neurotoxins (Prostaglandins A1 and E2, Hydrogen Peroxide and nitric oxide) in differentiated neuroblastoma cells. J Neurosci Res 2003 (in press).|
|61||Le Couteur DG, Leighton PW, McCann SJ, Pond S. Association of a polymorphism in the dopamine-transporter gene with Parkinson's disease. Mov Disord 1997;12:760-3.|
|62||Yamamoto M, Kondo I, Ogawa N, Asanuma M, Yamashita Y, Mizuno Y. Genetic association between susceptibility to Parkinson's disease and alpha1-antichymotrypsin polymorphism. Brain Res 1997;759:153-5.|
|63||Costa P, Checkoway H, Levy D, Smith-Weller T, Franklin GM, Swanson PD, et al. Association of a polymorphism in intron 13 of the monoamine oxidase B gene with Parkinson disease. Am J Med Genet 1997;74:154-6.|
|64||Takakubo F, Yamamoto M, Ogawa N, Yamashita Y, Mizuno Y, Kondo I. Genetic association between cytochrome P450IA1 gene and susceptibility to Parkinson's disease. J Neural Transm Gen Sect 1996;103:843-9.|
|65||Marx J. New gene tied to common form of Alzheimer's. Science 1998;281:507-9.|
|66||McConnell LM, Koenig BA, Greely HT, Raffin TA. Genetic testing and Alzheimer disease: has the time come? Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics & Society. Nat Med 1998;4:757-9.|
|67||Lam YA, Pickart CM, Alban A, Landon M, Jamieson C, Ramage R, et al. Inhibition of the ubiquitin-proteasome system in Alzheimer's disease. Proc Natl Acad Sci USA 2000;97:9902-6.|
|68||McMillan PJ, Leverenz JB, Dorsa DM. Specific downregulation of presenilin 2 gene expression is prominent during early stages of sporadic late-onset Alzheimer's disease. Brain Res Mol Brain Res 2000;78:138-45.|
|69||Fraser P, Tu G, Levesque G. Molecular genetics of the presenilins in Alzheimer's disease. In: Christen Y, editor. Presenilins and Alzheimer's Disease. Berlin: Springer-Verlag; 1998. pp. 1-10.|
|70||Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P. Role of the proteasome in Alzheimer's disease. Biochim Biophys Acta 2000;1502:133-8.|
|71||Rockwell P, Yuan H, Magnusson R, Figueiredo-Pereira ME. Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). Arch Biochem Biophys 2000;374:325-33.|
|72||Gregori L, Hainfeld JF, Simon MN, Goldgaber D. Binding of amyloid beta protein to the 20 S proteasome. J Biol Chem 1997;272:58-62.|
|73||Lopez Salon M, Morelli L, Castano EM, Soto EF, Pasquini JM. Defective ubiquitination of cerebral proteins in Alzheimer's disease. J Neurosci Res 2000;62:302-10.|
|74||Nahreini P, Andreatta C, Prasad KN. Proteasome activity is critical for the cAMP-induced differentiation of neuroblastoma cells. Cell Mol Neurobiol 2001;21:509-21.|
|75||Wang GP, Khatoon S, Iqbal K, Grundke-Iqbal I. Brain ubiquitin is markedly elevated in Alzheimer disease. Brain Res 1991;566:|
|77||Goedert M, Jakes R, Crowther RA, Six J, Lubke U, Vandermeeren M, et al. The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci U S A 1993;90:5066-70.|
|78||Borroni B, Colciaghi F, Lenzi GL, Caimi L, Cattabeni F, Di Luca M, et al. High cholesterol affects platelet APP processing in controls and in AD patients. Neurobiol Aging 2003;24:631-6.|
|79||Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M , Manjon M, et al. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 2003;61:199-205.|
|80||Austen BM, Sidera C, Liu, C. Frears E. The role of ontracellular cholesterol on the processing of the amyloid precursor protein. J Nutr Health Aging 2003;7:31-6.|
|81||Sparks DL, Martin TA, Gross DR, Hunsaker JC 3rd. Link between heart disease, cholesterol, and Alzheimer's disease: a review. Microsc Res Tech 2000;50:287-90.|
|82||Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000;356:1627-31.|
|83||Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, et al. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis 2000;7:321-31.|
|84||Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 1998;95:6460-4.|
|85||Kumar B, Andreatta C, Koustas WT, Cole WC, Edwards-Prasad J, Prasad KN. Mevastatin induces degeneration and decreases viability of cAMP-induced differentiated neuroblastoma cells in culture by inhibiting proteasome activity, and mevalonic acid lactone prevents these effects. J Neurosci Res 2002;68:627-35.|
|86||Sparks DL, Lochhead J, Horstman D, Wagoner T, Martin T. Water quaility has a pronounced effect on cholesterol-induced accumulation of Alzheimer amyloid beta (Abeta) in rabbit brain. J Alzheimers Dis 2002;4:523-9.|
|87||Vatassery GT, Brin MF, Fahn S, Kayden HJ, Traber MG. Effect of high doses of dietary vitamin E on the concentrations of vitamin E in several brain regions, plasma, liver, and adipose tissue of rats. J Neurochem 1988;51:621-3.|
|88||Pillai SR, Traber MG, Steiss JE, Kayden HJ, Cox NR. Alpha-tocopherol concentrations of the nervous system and selected tissues of adult dogs fed three levels of vitamin E. Lipids 1993;28:1101-5.|
|89||Cadet JL, Katz M, Jackson-Lewis V, Fahn S. Vitamin E attenuates the toxic effects of intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats: behavioral and biochemical evidence. Brain Res 1989;476:10-5.|
|90||Perumal AS, Gopal VB, Tordzro WK, Cooper TB, Cadet JL. Vitamin E attenuates the toxic effects of 6-hydroxydopamine on free radical scavenging systems in rat brain. Brain Res Bull 1992;29:699-701.|
|91||Schubert D, Kimura H, Maher P. Growth factors and vitamin E modify neuronal glutamate toxicity. Proc Natl Acad Sci USA 1992;89:8264-7.|
|92||O'hare E, McDiad D, Wilson R, Kennedy F, Kim E. Chronic alpha-tocopherol administrtion protects against behavioral impairment induced following intra-hipocampal Aß injection. Presented at Society for Neuroscience Annual Meeting: 2000. pp. 1788a.|
|93||Martin A, Cuervo A, Dice J, Joseph J. Effect of vitamin C on intracellular protein turnover in human glial cells. Presented at Society for Neuroscience Annual Meeting: 2000. pp. 1830a.|
|94||Fahns S. An open trial of high-dosage antioxidants in early Parkinson's disease. Am J Clin Nutr 1991;53:380S-2S. |
|95||Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N Engl J Med 1993;328:176-83.|
|96||Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 1997;336:1216-22.|
|97||Ingold KU, Burton GW, Foster DO, Hughes L, Lindsay DA, Webb A. Biokinetics of and discrimination between dietary RRR- and SRR-alpha-tocopherols in the male rat. Lipids 1987;22:163-72.|
|98||Prasad KN, Kumar B, Yan XD, Hanson AJ, Cole WC. Alpha-Tocopheryl succinate, the most effective form of Vitamin E for adjuvant cancer treatment: A Review. J Am Coll Nutr 2003;22:108-17.|
|99||Krinsky NI. Antioxidant functions of carotenoids. Free Radic Biol Med 1989;7:617-35.|
|100||Zhang LX, Cooney RV, Bertram JS. Carotenoids up-regulate connexin43 gene expression independent of their provitamin A or antioxidant properties. Cancer Res 1992;52:5707-12.|
|101||Vile GF, Winterbourn CC. Inhibition of adriamycin-promoted microsomal lipid peroxidation by beta-carotene, alpha-tocopherol and retinol at high and low oxygen partial pressures. FEBS Lett 1988;238:353-6.|
|102||McCay PB. Vitamin E: interactions with free radicals and ascorbate. Annu Rev Nutr 1985;5:323-40.|
|103||Perry TL, Godin DV, Hansen S. Parkinson's disease: a disorder due to nigral glutathione deficiency? Neurosci Lett 1982;33:305-10.|
|104||Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992;43:667-9.|
|105||Niki E. Mechanisms and dynamics of antioxidant action of ubiquinol. Mol Aspects Med 1997;18:S63-70.|
|106||Stoyanovsky DA, Osipov AN, Quinn PJ, Kagan VE. Ubiquinone-dependent recycling of vitamin E radicals by superoxide. Arch Biochem Biophys 1995;323:343-51.|
|107||Chen RS, Huang CC, Chu NS. Coenzyme Q10 treatment in mitochondrial encephalomyopathies. Short-term double-blind, crossover study. Eur Neurol 1997;37:212-8.|
|108||Birkmayer W, Birkmayer JGD, Vrecko C, Paletta B, Reschenhofer E, Ott E. Nicotinamide adenine dinucleotide (NADH) as medication for Parkinson's disease. Experience with 415 patients. New Trends Clin Neuropharmacol 1990;4:7-24.|
|109||Birkmayer W, Birkmayer JG, Vrecko K, Paletta B. The clinical benefit of NADH as stimulator of endogenous L-dopa biosynthesis in parkinsonian patients. In: Youdim MBH, editor. Advances in Neurology, Parkinson's Disease: Anatomy, Pathology, and Therapy. New York: Raven Press; 1990. pp. 545-9.|
|110||Vrecko K, Birkmayer JG, Krainz J. Stimulation of dopamine biosynthesis in cultured PC 12 phaeochromocytoma cells by the coenzyme nicotinamide adeninedinucleotide (NADH). J Neural Transm Park Dis Dement Sect 1993;5:147-56.|
|111||Birkmayer JG. Coenzyme nicotinamide adenine dinucleotide: new therapeutic approach for improving dementia of the Alzheimer type. Ann Clin Lab Sci 1996;26:1-9.|
|112||Regland B, Gottfries CG, Oreland L. Vitamin B12-induced reduction of platelet monoamine oxidase activity in patients with dementia and pernicious anaemia. Eur Arch Psychiatry Clin Neurosci 1991;240:288-91.|
|113||Nadeau A, Roberge AG. Effects of vitamin B12 supplementation on choline acetyltransferase activity in cat brain. Int J Vitam Nutr Res 1988;58:402-6.|
|114||Ikeda T, Yamamoto K, Takahashi K, Kaku Y, Uchiyama M, Sugiyama K, et al. Treatment of Alzheimer-type dementia with intravenous mecobalamin. Clin Ther 1992;14:426-37.|