Inhibition of Monoamine Oxidase Contributes to the Protective Effect of 7‐Nitroindazole Against MPTP Neurotoxicity

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.