Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine

Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H2O2)to water. In the present study we examined the susceptibility of mice with a disruption of the glutathion e peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic a cid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutat hione 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 hom ozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-o ut and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid, an index of hydroxyl radi cal generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Adminis tration of MPTP resulted in significantly greater depletions of dopamine, 3 ,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice tha n those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) con centrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resu lted in significantly greater striatal damage and increases in 3-NT in GSHP x knockout mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nons tressed conditions, but that after administration of mitochondrial toxins G SHPx plays an important role in detoxifying increases in oxygen radicals.