Inhibition of Neuronal Nitric Oxide Synthase by 7-Nitroindazole Protects Against MPTP-Induced Neurotoxicity in Mice |
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Authors: | Jö rg B. Schulz,Russell T. Matthews,Miratul M. K. Muqit,Susan E. Browne, M. Flint Beal |
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Affiliation: | Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A. |
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Abstract: | Abstract: Several studies suggest that nitric oxide (NO•) contributes to cell death following activation of NMDA receptors in cultured cortical, hippocampal, and striatal neurons. In the present study we investigated whether 7-nitroindazole (7-NI), a specific neuronal nitric oxide synthase inhibitor, can block dopaminergic neurotoxicity seen in mice after systemic administration of MPTP. 7-NI dose-dependently protected against MPTP-induced dopamine depletions using two different dosing regimens of MPTP that produced varying degrees of dopamine depletion. At 50 mg/kg of 7-NI there was almost complete protection in both paradigms. Similar effects were seen with MPTP-induced depletions of both homovanillic acid and 3,4-dihydroxyphenylacetic acid. 7-NI had no significant effect on dopamine transport in vitro and on monoamine oxidase B activity both in vitro and in vivo. One mechanism by which NO• is thought to mediate its toxicity is by interacting with superoxide radical to form peroxynitrite (ONOO−), which then may nitrate tyrosine residues. Consistent with this hypothesis, MPTP neurotoxicity in mice resulted in a significant increase in the concentration of 3-nitrotyrosine, which was attenuated by treatment with 7-NI. Our results suggest that NO• plays a role in MPTP neurotoxicity, as well as novel therapeutic strategies for Parkinson's disease. |
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Keywords: | MPTP Excitotoxicity Parkinson's disease Nitric oxide synthase Free radicals Energy impairment 7-Nitroindazole |
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