Inhibition of Monoamine Oxidase Contributes to the Protective Effect of 7-Nitroindazole Against MPTP Neurotoxicity |
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Authors: | Donato A. Di Monte Joyce E. Royland Andrea Anderson Kay Castagnoli Neal Castagnoli Jr. J. William Langston |
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Affiliation: | The Parkinson's Institute, Sunnyvale, California;and; Harvey W. Peters Center, Department of Chemistry, Virginia Polytechnic Institute, Blacksburg, Virginia, U.S.A. |
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Abstract: | Abstract: The ability of 7-nitroindazole (7-NI) to protect against MPTP-induced neurotoxicity has been attributed to its inhibition of neuronal nitric oxide synthase. In the present study, 7-NI was found to counteract almost completely striatal dopamine depletion caused by a single subcutaneus injection of 20 mg/kg MPTP in mice. This effect, however, was accompanied by a significant reduction in the striatal levels of MPP+, the toxic metabolite generated via monoamine oxidase B-catalyzed MPTP oxidation. In the presence of 7-NI, a dose of 40 mg/kg MPTP produced MPP+ concentrations similar to those measured after treatment with 20 mg/kg MPTP alone. A comparison of neurotoxicity in these two experimental conditions (i.e., mice treated with 20 mg/kg alone versus 40 mg/kg MPTP plus 7-NI) revealed only a slight (20%), but statistically significant, protection of dopamine depletion with 7-NI. These data indicate that the mechanism by which 7-NI counteracts MPTP neurotoxicity in mice is not due solely to inhibition of neuronal nitric oxide synthase, but involves a reduction in MPP+ formation. |
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Keywords: | MPTP Monoamine oxidase Nitric oxide 7-Nitroindazole Neuroprotection Parkinsonism |
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