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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. 2000 Jan 01; 20(1):1-7.JN

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.

Authors+Show Affiliations

Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10627575

Citation

Klivenyi, P, et al. "Mice Deficient in Cellular Glutathione Peroxidase Show Increased Vulnerability to Malonate, 3-nitropropionic Acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 20, no. 1, 2000, pp. 1-7.
Klivenyi P, Andreassen OA, Ferrante RJ, et al. 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. 2000;20(1):1-7.
Klivenyi, P., Andreassen, O. A., Ferrante, R. J., Dedeoglu, A., Mueller, G., Lancelot, E., Bogdanov, M., Andersen, J. K., Jiang, D., & Beal, M. F. (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. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 20(1), 1-7.
Klivenyi P, et al. 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. 2000 Jan 1;20(1):1-7. PubMed PMID: 10627575.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. AU - Klivenyi,P, AU - Andreassen,O A, AU - Ferrante,R J, AU - Dedeoglu,A, AU - Mueller,G, AU - Lancelot,E, AU - Bogdanov,M, AU - Andersen,J K, AU - Jiang,D, AU - Beal,M F, PY - 2000/1/11/pubmed PY - 2000/1/11/medline PY - 2000/1/11/entrez SP - 1 EP - 7 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 20 IS - 1 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/10627575/Mice_deficient_in_cellular_glutathione_peroxidase_show_increased_vulnerability_to_malonate_3_nitropropionic_acid_and_1_methyl_4_phenyl_1256_tetrahydropyridine_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10627575 DB - PRIME DP - Unbound Medicine ER -