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

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.

Fig. 1.

Malonate induced striatal lesion volumes in wild-type controls, heterozygote, and homozygote GSHPx knock-out mice. **p < 0.01, as compared with controls; #p < 0.05, as compared with heterozygote GSHPx knock-out mice.

Fig. 2.

Malonate induced increases in the conversion of salicylate to 2,3 and 2,5-DHBA in wild-type controls, heterozygote, and homozygote GSHPx knock-out mice. *p < 0.001, as compared with the uninjected striatum; #p < 0.001, as compared with heterozygote GSHPx knock-out and wild-type controls.

Fig. 3.

Effects of MPTP administered at 15 mg/kg X4 on dopamine, DOPAC, and HVA in wild-type control and GSHPx knock-out mice. *p < 0.05, ***p < 0.001, as compared to PBS-treated animals; ##p < 0.01, ###p < 0.001, as compared to wild-type treated with MPTP.

Fig. 4.

Effects of MPTP 20 mg/kg X2 on striatal 3-NT levels 2 hr after MPTP administration in wild-type control and GSHPx knock-out mice. **p < 0.01, as compared with wild-type controls.

Fig. 5.

Photomicrographs of 3-NP lesions in Nissl-stained whole-brain sections through the striatum of wild-type (A) and glutathione peroxidase knock-out (B) mice. Bilateral striatal lesions are present in both A and B and are represented by staining pallor in the lateral aspect (arrows). The lesions are significantly larger in the glutathione peroxidase knock-out mouse. Scale bar, 2 mm.

Fig. 6.

Effects of 3-NP on 3-NT levels in wild-type control and GSHPx knock-out mice. **p < 0.01, ***p < 0.001, as compared with PBS; #p < 0.05, as compared with wild-type control.