Treatment with 7-nitroindazole enhances kainic acid induced cholinergic neurotoxicity in the rat striatum: a neuroprotective role for neuronal nitric oxide.
1. In this study we investigated the effect of 7-nitroindazole (7-NI), a preferential inhibitor of neuronal nitric oxide synthase (nNOS), on kainic acid (KA) induced neurotoxicity in rats. Choline acetyltransferase activity (CAT), a cholinergic marker, and histological changes were employed to assess neurotoxicity. 2. In control rats, the local intrastriatal injection of 0.5 microg of KA reduced CAT from 22.9 +/- 2.2 to 14.7 +/- 2.0 nmol/h/mg tissue ((38 +/- 6)% reduction) (P < 0.001). Greater reductions in CAT were observed with 1 and 2 microg of KA ((70 +/- 6)% and (80 +/- 3)%, respectively). 7-NI aggravated KA-induced cholinergic and histological damage. KA reduced CAT by (68.2 +/- 4)% in 7-NI-treated rats, by (38 +/- 6)% in saline-treated controls, and by (41 +/- 4)% in peanut-oil- (7-NI-vehicle-) treated rats (P = 0.0047). 3. After KA, CAT activity averaged 14.3 +/- 2.0 in peanut-oil-treated rats and 7.9 +/- 1.0 nmol/h/mg tissue in 7-NI- (peanut-oil-) treated rats (P = 0.015). Similarly to changes in CAT, 7-NI treatment aggravated KA-induced histological changes indicative of neuronal damage (acute ischemic neuronal changes, disorganization of myelinated fibers bundle, and vacuolation changes of the neuropil). Treatment with 7-NI was not associated with increased mortality. 4. Our findings suggest that neuronal NO plays a neuroprotective action on excitotoxicity.
Guevara
Beatriz H
BH
Neuropharmacology Unit, Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Caracas, Venezuela.
Cespedes
Ghislaine C
GC
Cubeddu
Luigi X
LX
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007191:Indazoles / Q000633:toxicity*; D007608:Kainic Acid / Q000633:toxicity*; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D007191:Indazoles; D009498:Neurotoxins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D002795:Choline O-Acetyltransferase; D007608:Kainic Acid; C080122:7-nitroindazole