Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTP-induced neurotoxicity. The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.
Przedborski
S
S
Department of Neurology, Columbia University, New York 10032, USA. sp30@columbia.edu
Jackson-Lewis
V
V
Yokoyama
R
R
Shibata
T
T
Dawson
V L
VL
Dawson
T M
TM
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000209:etiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D007191:Indazoles; D007527:Isoenzymes; D015102:3,4-Dihydroxyphenylacetic Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole; D004298:Dopamine; D006719:Homovanillic Acid