7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced ATP loss in the mouse striatum.
The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is dependent upon the MAO-B (monoamine oxidase type B)-catalyzed production of 1-methyl-4-phenylpyridinium ion (MPP(+)) and is likely to involve a perturbation of energy metabolism. Protection against MPTP neurotoxicity has been shown by treating mice with 7-nitroindazole (7-NI), a reversible inhibitor of both MAO-B and neuronal nitric oxide synthase (nNOS) activity. The objective of the present study was to evaluate (i) the relationship between the neuroprotective effect of 7-NI and MPTP-induced energy deficiency, and (ii) the role of nitric oxide production as a potential mechanism for energy perturbation after MPTP exposure. Maximum protection against striatal dopamine depletion and nigral neuronal loss was achieved when 7-NI (50 mg/kg, i.p.) was administered to C57BL/6 mice immediately before and after MPTP (50 mg/kg, s.c.). This short-term regimen of 7-NI administration parallels the time when MPTP exposure causes energy failure. 7-NI also completely prevented the loss of striatal ATP that occurs in mice during the initial hours after MPTP administration. In contrast, N(G)-nitro-L-arginine (two injections of 50 mg/kg each, given i.p. 20 and 4 h prior to MPTP), another NOS inhibitor, failed to affect MPTP-induced ATP depletion. Taken together, data indicate that (i) a temporal and causal relationship exists between the neuroprotective effect of 7-NI and its ability to counteract ATP reduction, and (ii) MAO-B rather than NOS inhibition is the mechanism by which 7-NI counteracts MPTP-induced ATP depletion.
Royland
J E
JE
The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA, USA.
Delfani
K
K
Langston
J W
JW
Janson
A M
AM
Di Monte
D A
DA
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D019335:Nitroarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007191:Indazoles; D018696:Neuroprotective Agents; D019335:Nitroarginine; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C080122:7-nitroindazole