The goal of the Unit on Neurotoxicology and Neuroprotection is to develop practical neuroprotective strategies for preserving brain neurons from oxidative stress caused by cytotoxic oxygen free radicals (NO and OH). In addition to the laboratory research summarized below, and in response to the Decade of the Brain proclamation, we organized an international Symposium on the Neurobiology of NO and OH Free Radicals to discuss current research on neuroprotective strategies in the treatment of oxidant- induced brain disorders (November, 1993, Bethesda). Supporting the use of antioxidants in clinical trials on neuroprotection, the present data demonstrate that antioxidants can protect brain neurons against in vivo lipid peroxidation and cell injury induced by reactive oxygen species. Our in vivo free radical trapping procedure revealed that both the dopaminergic neurotoxin, MPP+ and a small mass iron complex, ferrous citrate, increased the generation of hydroxyl radicals that lead to the peroxidation of polyunsaturated fatty acid in the brain. This free radical chain reaction or lipid peroxidation subsequently causes oxidative neuronal injury. The present results indicate that the iron complex is as toxic as MPP+ in causing degeneration of the nigrostriatal dopaminergic neurons. This free radical induced lipid peroxidation and neuronal death through calcium cascade and/or apoptosis was significantly suppressed by antioxidants (e.g., U-78517F and alpha-lipoic acid) and atypical antioxidants which are also monoamine oxidase inhibitors (e.g., deprenyl and pargyline). The exact neurorescue mechanisms of l-deprenyl are quite complicated and remain unelucidated. The present data support our working hypothesis that reactive oxygen species and related oxidative chain reactions could play a role in neurodegenerative disorders, such as Parkinson's disease. In addition, we demonstrated that novel neuroprotective antioxidants protect brain neurons against oxidative injury, and this implies that antioxidants could be used therapeutically to slow and/or halt progressive disabilities due to neurodegeneration. It is hoped that a neurorescue strategy developed from this research may eventually improve the quality of life for patients suffering from progressive deterioration in cognitive and/or cerebral motor function.
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