A study of the dose dependency of a glycine receptor antagonist in focal ischemia.
N-methyl-D-aspartate receptor antagonists are potent neuroprotectants in experimental focal cerebral ischemia, but behavioral and neuropathologic changes seen with these drugs in rodent models may limit the clinical utility of these compounds. Glycine's modulation of N-methyl-D-aspartate channel function offers another pharmacologic approach to excitotoxicity in ischemia. The potent glycine antagonist 7 Chlorothiokynurenic acid (7-Cl-Thio-Kyna) was studied in a permanent middle cerebral artery occlusion stroke model in the rat. The compound was effective, in a dose-dependent manner, in attenuating infarct size when administered before or after permanent middle cerebral artery occlusion. Its activity was mainly due to glycine antagonism inasmuch as 5 Chlorothiokynurenic acid, a compound having other pharmacological activities in common with 7-CI-Thio-Kyna (for instance the radical scavenger action), was inactive in this model. 7-Cl-Thio-Kyna did not produce cytological changes similar to MK 801.
Chen
J
J
Department of Neurology, University of California, San Francisco.
Graham
S
S
Moroni
F
F
Simon
R
R
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry; D001927:Brain Diseases / Q000139:chemically induced; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers; D006360:Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis; D007150:Immunohistochemistry; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*
D016166:Free Radical Scavengers; D006360:Heat-Shock Proteins; D018009:Receptors, Glycine; C084485:7-chlorothiokynurenic acid; C084484:5-chlorothiokynurenic acid; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid