Mechanisms involved in the neuroprotective activity of a nitric oxide synthase inhibitor during focal cerebral ischemia.
We have reported previously that posttreatment with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the nitric oxide synthase, reduced the volume of cortical and striatal infarct induced by middle cerebral artery occlusion in rats. In the present study, we investigated the mechanisms by which L-NAME (3 mg/kg i.p.) is neuroprotective in this model of cerebral ischemia. First, we have shown the reversal of the neuroprotective effect of L-NAME by a coinjection of L-arginine. Second, in order to determine by which mechanism nitric oxide exacerbates neuronal damage produced by focal cerebral ischemia, we studied the effect of the inhibition of nitric oxide synthase by L-NAME on the histological consequences of a focal injection of N-methyl-D-aspartate (NMDA) in the striatum, and on the striatal overflow of glutamate and aspartate induced either by K+ depolarization or by focal cerebral ischemia. We have found that L-NAME treatment reduced the excitotoxic damage produced by NMDA injection. By using microdialysis, we have shown that the K(+)- and the ischemia-induced glutamate efflux was reduced by 52 and 30%, respectively, after the L-NAME treatment. These results indicate that nitric oxide synthesis induced by the NMDA receptor overstimulation is one of the major events leading to neuronal damage. One possible mechanism by which nitric oxide may contribute to the excitotoxic process is by facilitating the ischemia-induced glutamate overflow.
Buisson
A
A
Laboratoire de Pharmacologie, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France.
Margaill
I
I
Callebert
J
J
Plotkine
M
M
Boulu
R G
RG
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001224:Aspartic Acid / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology*; D007700:Kinetics; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology
D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester