7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ATP loss in the mouse striatum

Citation
Je. Royland et al., 7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ATP loss in the mouse striatum, BRAIN RES, 839(1), 1999, pp. 41-48
Citations number
31
Categorie Soggetti
Neurosciences & Behavoir
Journal title
BRAIN RESEARCH
ISSN journal
00068993 → ACNP
Volume
839
Issue
1
Year of publication
1999
Pages
41 - 48
Database
ISI
SICI code
0006-8993(19990821)839:1<41:7P1>2.0.ZU;2-8
Abstract
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 o f 1-methyl-4-phenylpyridinium ion (MPP+) and is likely to involve a perturb ation 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 objec tive 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 pe rturbation after MPTP exposure. Maximum protection against striatal dopamin e 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 ti me when MPTP exposure causes energy failure. 7-NI also completely prevented the loss of striatal ATP that occurs in mice during the initial hours afte r 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 indicat e that (i) a temporal and causal relationship exists between the neuroprote ctive effect of 7-NI and its ability to counteract ATP reduction, and (ii) MAO-B rather th;in NOS inhibition is the mechanism by which 7-NI counteract s MPTP-induced ATP depletion. (C) 1999 Elsevier Science B.V. All rights res erved.