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Oxident stress,due to the formation of hydrogen peroxide and oxygen- derived free radicals,can cause cell damage due to chain reactions of membrane lipid peroxidation.Because the substantia nigra is rich in dopamine,which can undergo both enzymatic oxidation via monoamine oxidase and nonenzymatic autoxidation,hydrogen peroxide and oxyradicals(superocide anion radical and hydroxyl radical)are generated in this midbrain nucleus. Although proof that oxident stress actually causes the loss of monoaminergic neurons in patients with parkinson's disease is lacking, there is a considerable body of evidence from studies in both animals and humans that support the concept(1)Neurotoxins that selectively destroy the dopaminergic neurons in the nigra,such as 6-hydroxydopamine and 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine(MPTP),appear to act via oxident stress,(2)The substantia nigra of patients with Parkinson's disease reveals evidence of oxidant stress by the findings of increased lipid peroxidation and decreased reduced glutathione.(3)Total iron is increased and ferritin is reduced in the substantia nigra pars compacta in aptients with Parkinson's disease.This combination suggests that this transition metal is in a low molecular weight form,capable of catalyzing nonenzymatic oxidative reactions,especially the conversion of hydrogen peroxide to hydroxyl radical,which is the most reactive of the ozygen radicals.(4) Neuromelanin,a product of dopamine autoxidation,can serve as a reservois for iron,promoting the generation of oxyradicals.(5)Antioxident defense mechanisms appear to be reduced in the parkinsonian substantia nigra with the findings of decreased activities of glutathione peroxidase and catalase.(6)The recent findings of decreased activity of NADH-CoQ reductase,a mitochondrial complex I enzyme,in substantia nigra and platelets in patients with Parkinson's disease can also be interpreted to be a cuase of product of oxidant stress.The identical enzyme abnormality occurs with MPTP toxicity,and this has been associated with increased superoxide anion radical formation.Moreover,mice with increased activity of superoxide dismutase are protected against MPTP toxicity.The evidence favring the oxidant stress hypothesis is persuasive,but not yet fully established.We believe that this is the best hypothesis available at present. |
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DATATOP study
free radical
Parkinson disease,etiology of
Parkinson disease,pathogenesis of
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