Inhibition of monoamine oxidase contributes to the protective effect of 7-nitroindazole against MPTP neurotoxicity.
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.
Di Monte
D A
DA
The Parkinson's Institute, Sunnyvale, California 94089, U.S.A.
Royland
J E
JE
Anderson
A
A
Castagnoli
K
K
Castagnoli
N
N
Langston
J W
JW
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007191:Indazoles; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019001:Nitric Oxide Synthase; D015655:1-Methyl-4-phenylpyridinium; C080122:7-nitroindazole