The nervous system, including the brain, spinal cord, and peripheral nerves, is rich in both unsaturated fats (which are prone to oxidation) and iron (Halliwell 1992). The high lipid content of nervous tissue, coupled with its high metabolic (aerobic) activity, makes it particularly susceptible to oxidant damage (Dawson and Dawson 1996). The high level of brain iron may be essential, particularly during development, but its presence also means that injury to brain cells may release iron ions that can lead to oxidative stress via the iron-catalyzed formation of reactive oxygen species (Gerlach et al. 1994).

There is substantial evidence that oxidative stress is a causative or at least ancillary factor in the pathogenesis of major neurodegenerative diseases, including Parkinson's disease (Ebadi et al. 1996), Alzheimer's disease (Markesbery and Carney 1999; Behl 1999), and amyotrophic lateral sclerosis (ALS, "Lou Gehrig's disease") (Olanow and Arendash 1994; Simonian and Coyle 1996; Hall et al. 1998) as well as in cases of stroke, trauma, and seizures (Coyle and Puttfarcken 1993; Facchinetti et al. 1998). Decreased levels of antioxidant enzyme activity are found in Parkinson's disease patients (Fahn and Cohen 1992). Evidence of oxidative stress in the form of increased lipid peroxidation and oxidation of DNA bases is seen in the substantia nigra, the area of the brain affected in Parkinson's disease (Jenner 1996). Similar increased lipid peroxidation and oxidation of DNA and proteins are seen in Alzheimer's disease (Retz et al. 1998) and in Huntington's disease (Borlongan et al. 1996). Increases in markers of oxidative stress (e.g., oxidation of proteins or of DNA) are seen in both familial ALS (FALS) and sporadic ALS (SALS) patients (Ferrante et al. 1997). It has been suggested that Alzheimer's disease may be linked to diet, with reduced risk associated with diets high in antioxidants (Grant 1997).

A number of in vitro studies have shown that antioxidants, both endogenous and dietary, can protect nervous tissue from damage by oxidative stress. Uric acid, an endogenous antioxidant, was found to prevent neuron damage in rats, both in vitro and in vivo, from the metabolic stresses of ischemia (oxidative stress as well as exposure to the excitatory amino acid glutamate and the toxic compound cyanide) (Yu et al. 1998). Vitamin E was found to prevent cell death (apoptosis) in rat neurons subjected to hypoxia followed by oxygen reperfusion (Tagami et al. 1998). The same study showed that vitamin E prevented neuronal damage from reactive nitrogen species (Tagami et al. 1998). Both vitamin E and beta-carotene were found to protect rat neurons against oxidative stress from exposure to ethanol (Mitchell et al. 1999). In an experimental model of diabetes-caused neurovascular dysfunction, beta-carotene was found to protect cells most effectively, followed by vitamin E and vitamin C (Cotter et al. 1995).

Most in vivo and clinical studies of the effects of lipid-soluble antioxidant supplementation on neurological diseases have focused on vitamin E. A report in 1991 demonstrated that the rate at which Parkinson's disease progressed to the point when the patient required treatment with levodopa was slowed by 2.5 years in patients given large doses of vitamin C and synthetic vitamin E (Fahn 1991). Although one study reported that high doses of vitamin E resulted in elevated plasma levels but failed to increase vitamin E levels in cerebrospinal fluid (CSF) (Pappert et al. 1996), a later report demonstrated that high doses of vitamin E did result in elevation of CSF vitamin E levels, and possibly brain vitamin E levels (Vatassery et al. 1998). Recently it was shown that the protein responsible for the uptake of Vitamin E is in fact present in brain cells of patients suffering from Vitamin E deficiency or diseases associated with oxidative stress (Copp et al. 1999). In a Dutch study, it was found that the risk for Parkinson's disease was lower for subjects who had higher dietary intakes of antioxidants, particularly vitamin E (de Rijk et al. 1997). The same group reported that a low dietary intake of beta-carotene was associated with impaired cognitive function in a group of persons aged 55-95; no such association was observed for either vitamins C or E (Jama et al. 1996). In an Austrian study, serum concentration of Vitamin E was found to be significantly associated with cognitive function in adults aged 50 - 75 years measured by a standardized test; serum concentrations of lutein/zeaxanthin, cryptoxanthin, canthaxanthin, lycopene, alpha-carotene, beta-carotene, retinol, gamma-tocopherol, and ascorbate had no significant effects (Schmidt et al. 1998). In another study, it was found that patients suffering from Parkinson's disease had consumed less of the small-molecule antioxidants beta-carotene and vitamin C than did non-sufferers of the disease, implying that dietary antioxidants do play a protective role in this disease (Hellenbrand et al. 1996). About 20% of FALS cases are associated with a mutation in the gene for copper/zinc superoxide dismutase, an important antioxidant enzyme, and in vitro experiments demonstrated that expression of the mutant enzyme in neuronal cells caused cell death, which could be prevented by antioxidant small molecules such as glutathione and vitamin E (Ghadge et al. 1997).

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