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 accepted as a major mechanism of ischemic neuronal damage. MK-801 and mild hypothermia, two cerebroprotective modalities, which have been documented to alter glutamatergic action, were tested in the rat middle cerebral artery occlusion (MCAO) model simulating permanent focal ischemia. We administered normothermic (37°C) animals with either MK-801 (1.0 mg/kg 30 min before MCAO or 2.5 mg/kg 30 min before, immediately after, 4 hours, and 8 hours after MCAO) or saline vehicle (30 min before MCAO). Mildly hypothermic (33°C) animals were administered 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; their brains were sectioned and stained with 2,3,5-triphenyltetrazolium chloride and their infarct volumes were calculated. In normothermica animals given 1.0 mg/kg and multidose 2.5-mg/kg intraperitoneal injections of MK-801, the infarct volumes (as a percentage of right hemispheric volume) were 16.8 ± 3.5% and 16.3 ± 3.0%, respectively. These infarct volumes were significantly different (P < 0.05; single-variable analysis 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) confirmed the same significant differences in infarct size. The infarct volumes from the mildly hypothermic groups were not different (1 mg/kg of MK-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 was significantly reduced compared with the normothermic drug-free control (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 ischemia model, it appears that mild hypothermia and MK-801 offer similar cerebroprotective effects when administered separately, but do not yield additive effects when used in combination.