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 (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.
Klivenyi
P
P
Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Andreassen
O A
OA
Ferrante
R J
RJ
Dedeoglu
A
A
Mueller
G
G
Lancelot
E
E
Bogdanov
M
M
Andersen
J K
JK
Jiang
D
D
Beal
M F
MF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002396:Catechols / Q000032:analysis; D003292:Convulsants / Q000633:toxicity*; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics*; D006579:Heterozygote; D006719:Homovanillic Acid / Q000032:analysis; D006720:Homozygote; D006816:Huntington Disease / Q000235:genetics; D020267:MPTP Poisoning / Q000235:genetics*; D008297:Male; D008314:Malonates / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010302:Parkinson Disease, Secondary / Q000235:genetics; D011422:Propionates / Q000633:toxicity*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D002396:Catechols; D003292:Convulsants; D015259:Dopamine Agents; D005609:Free Radicals; D008314:Malonates; D009574:Nitro Compounds; D011422:Propionates; D015102:3,4-Dihydroxyphenylacetic Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C067001:2,4-dihydroxybenzylamine; C030290:malonic acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D005979:Glutathione Peroxidase; D005978:Glutathione; C015392:3-nitropropionic acid; D006719:Homovanillic Acid