MILD HYPOTHERMIA AND MK-801 HAVE SIMILAR BUT NOT ADDITIVE DEGREES OF CEREBROPROTECTION IN THE RAT PERMANENT FOCAL ISCHEMIA MODEL

ALTHOUGH NOT THE sole factor, glutamate-mediated excitotoxicity is acc epted as a major mechanism of ischemic neuronal damage. MK-801 and mil d hypothermia, two cerebroprotective modalities, which have been docum ented to alter glutamatergic action, were tested in the rat middle cer ebral artery occlusion (MCAO) model simulating permanent focal ischemi a. We administered normothermic (37 degrees C) animals with either MK- 801 (1.0 mg/kg 30 min before MCAO or 2.5 mg/kg 30 min before, immediat ely after, 4 hours, and 8 hours after MCAO) or saline vehicle (30 min before MCAO). Mildly hypothermic (33 degrees C) animals were administe red either MK-801 (1.0 mg/kg) or saline vehicle 30 minutes before MCAO . Mild hypothermia was induced over a 20-minute period before MCAO in hypothermic animals. All animals were killed 24 hours after MCAO; thei r brains were sectioned and stained with 2,3,5-triphenyltetrazolium ch loride and their infarct volumes were calculated. In normothermica ani mals given 1.0 mg/kg and multidose 2.5-mg/kg intraperitoneal injection s of MK-801, the infarct volumes ras a percentage of right hemispheric volume) were 16.8 +/- 3.5% and 16.3 +/- 3.0%, respectively. These inf arct volumes were significantly different (P < 0.05; single-variable a nalysis of variance) from the normothermic, drug-free control (26.8 +/ - 1.9%), but not significantly different from each other. Analysis of the data using a nonparametric test (Kruskal-Wallis; P = 0.02) confirm ed the same significant differences in infarct size. The infarct volum es from the mildly hypothermic groups were not different (1 mg/kg of M K-801, 15.5 +/- 2.3% and saline control, 15.4 +/- 1.1%). However, the percentage of infarct size in the mildly hypothermic drug-free group w as significantly reduced compared with the normothermic drug-free cont rol (P< 0.0005; two-tailed Student's t-test). There was no significant difference between normothermic and mildly hypothermic animals given 1 mg/kg of MK-801. Therefore, in a rat permanent focal cerebral ischem ia model, it appears that mild hypothermia and MK-801 offer similar ce rebroprotective effects when administered separately, but do not yield additive effects when used in combination.