Cerebroprotective effect of a non-N-methyl-D-aspartate antagonist, GYKI 52466, after focal ischemia in the rat.
OBJECTIVE
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-benzodiazep ine 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 less than 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 less than 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.
Smith
S E
SE
Department of Neurology, Institute of Psychiatry, Denmark Hill, UK.
Meldrum
B S
BS
D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D007262:Infusions, Intravenous; D008297:Male; D014677:Pharmaceutical Vehicles; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D014151:Anti-Anxiety Agents; D014677:Pharmaceutical Vehicles; C061950:GYKI 52466; D001569:Benzodiazepines