(ALS); manganese superoxide dismutase (Mn-SOD); Cu/Zn superoxide dismutase (Cu/Zn-SOD); hypochlorous acid (HOCl); nitric oxide synthase (NOS); 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP); copper chaperone for Cu/Zn superoxide dismutase (CCS). phenotype, because a multitude of repair processes can be activated to sustain physiological function. In keeping with this, succumbing neurons may be the least proficient in repair capacity. Consistent with this view is the demonstration of decreased repair activity of methionine sulfoxide reductase, an enzymatic activity essential for repair of oxidized methionine residues, in Alzheimer disease brains (8). Methionine sulfoxide reductase (9) or oxidized DNA-repair enzymes may regulate the lifespan of mammals, as mice with mutations in the XPD gene that encodes for a DNA helicase, which is involved in both repair of oxidized DNA lesions and transcription, show evidence of premature aging (10). Experimentally, the importance of the balance between oxidants and antioxidants has been primarily tested by two approaches in animal and cellular model systems: the genetic elimination of an antioxidant defense mechanism, and the augmentation of antioxidant defenses. In the first paradigm, downregulation of Cu/Zn superoxide dismutase (Cu/Zn-SOD) in mice and cells is associated with increased neuronal injury and death (11, 12). More serious consequences arise from the elimination of the mitochondrial Mn-SOD, which is generally lethal in the neonatal period (13). In addition to causing cardiac failure, the mitochondrial SOD knockout mouse suffers CNS pathology that includes mitochondrial vacuolization and oxidized lipid deposits (13). Mice deficient in glutathione peroxidase, an enzymatic pathway largely responsible for the elimination of hydrogen peroxide and fatty acid peroxides, are more sensitive to ischemia/reperfusion injury and neurotoxins (14). Recently, mice deficient in the α-tocopherol (ie, vitamin E) transport protein were shown to develop a delayed-onset ataxia and neurodegeneration (15). Conversely, intake of vitamin E has been found to retard the clinical progression of Alzheimer disease (16), and to offer small but significant benefit in ALS patients taking riluzole (17). Recently, treatment with dehydroascorbate has been shown to be protective against stroke (18). Dehydroascorbate was used because it is rapidly taken up into the brain and is reduced to ascorbate. Deficiency in the ascorbate transporter in mice causes lethal cerebral hemorrhages shortly after birth (19). Metals such as copper and zinc have been shown to accelerate amyloid deposition (20). Redox-active metals such as copper and iron have been implicated in a variety of oxidative processes including Aβ peptide–induced protein oxidation (20) and inactivation of putative antioxidant defenses such as heme oxygenase (21). Chelation of copper by the antibiotic iodochlorhydroxyquin (Clioquinol) has been found to effectively retard amyloid deposition in a mouse model of Alzheimer disease (22). Genetic and biochemical manipulations to enhance antioxidant defenses provide sound support for the hypothesis that oxidative stress is a critical and common mechanism in neurodegeneration. Overexpression of Cu/Zn-SOD in transgenic mice and rats provides substantial protection against ischemia, cold edema, and neurotoxins and promotes survival of neurons in culture and after transplantation (23–25). Genetically induced increase in expression of Mn-SOD (26) or induction of the enzyme during stress (27) has been shown to protect mitochondria and cells from oxidative stress. Similarly, increased expression …