PMID:10627575

Citation	Klivenyi, P, Andreassen, OA, Ferrante, RJ, Dedeoglu, A, Mueller, G, Lancelot, E, Bogdanov, M, Andersen, JK, Jiang, D and Beal, MF (2000) Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. J. Neurosci. 20:1-7
Abstract	Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.
Links	PubMed
Keywords	1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology; 3,4-Dihydroxyphenylacetic Acid/analysis; Animals; Brain Chemistry/drug effects; Brain Chemistry/genetics; Catechols/analysis; Convulsants/toxicity; Corpus Striatum/chemistry; Corpus Striatum/drug effects; Corpus Striatum/enzymology; Disease Models, Animal; Dopamine Agents/pharmacology; Female; Free Radicals/metabolism; Glutathione/metabolism; Glutathione Peroxidase/genetics; Heterozygote; Homovanillic Acid/analysis; Homozygote; Huntington Disease/genetics; MPTP Poisoning/genetics; Male; Malonates/toxicity; Mice; Mice, Inbred Strains; Mice, Knockout; Nitro Compounds; Oxidative Stress/drug effects; Oxidative Stress/genetics; Parkinson Disease, Secondary/genetics; Propionic Acids/toxicity; Tyrosine/analogs & derivatives; Tyrosine/analysis
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