CEREBROPROTECTIVE EFFECT OF A NON-N-METHYL-D-ASPARTATE ANTAGONIST, GYKI 52466, AFTER FOCAL ISCHEMIA IN THE RAT

Background and Purpose: Cerebroprotection after the administration of N-methyl-D-aspartate antagonists has been well documented. The present study sought to determine whether a cerebroprotective effect could be achieved with the administration of a non-N-methyl-D-aspartate antagonist, GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine hydrochloride; molecular weight, 330) after middle cerebral artery occlusion in the rat. Methods: Neurological deficit and infarct volume 24 hours after permanent left middle cerebral artery occlusion in Fischer rats (n=7-13 per group per dose) were studied. Cerebral infarcts was visualized by the lack of reduction of 2,3,5-triphenyltetrazolium chloride. Results: GYKI 52466 (10 mg . kg-1 i.p. at 0, 2, 4 hours) after middle cerebral artery occlusion had no effect on infarct volume. GYKI 52466 (10 mg . kg-1 i.v. for 5 minutes followed by 15 mg . kg-1 . hr-1 i.v. for 2 hours immediately after middle cerebral artery occlusion reduced cortical infarct volume by 68% (from 69 mm3 in vehicle-treated to 22 mm3 in GYKI 52466-treated animals; p<0.05). A 1-hour delay before initiation of drug infusion resulted in a 48% reduction in cortical infarct volume (from 60 mm3 vehicle-treated rats to 31 mm3 in GYKI 52466-treated rats; p < 0.05). A 2-hour delay before initiation of drug infusion had no effect on cortical infarct volume. Neurological deficits (with blinded assessment after 24 hours) were improved after immediate treatment and after delayed treatment (1 or 2 hours). Conclusions: The cerebroprotective effect of GYKI 52466 in the rat suggests a possible therapeutic role for non-N-methyl-D-aspartate antagonists given shortly after the onset of stroke.