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 nigrostriat al dopaminergic pathway damage similar to that observed in Parkinson d isease (PD). To study the role of NO radical in MPTP-induced neurotoxi city, 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 indice s of severe injury to the nigrostriatal dopaminergic pathway, includin g reduction in striatal dopamine contents, decreases in numbers of nig ral 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 si gnificantly 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 betw een the MPTP model and PD raises the possibility that NO may play a si gnificant role in the etiology of PD.