Mild hypothermia reduces penumbral glutamate levels in the rat permanent focal cerebral ischemia model

Abstract

Although the cerebroprotective effects of hypothermia in focal models of ischemia are undisputed, the underlying mechanisms of this protection are still subject to much controversy. To analyze whether mild hypothermia attenuates glutamate levels in the penumbra surrounding permanent focal infarcts, extracellular glutamate concentration was analyzed bilaterally by microdialysis 20 minutes before to 120 minutes after a middle cerebral artery occlusion (MCAO) in rats. Normothermic animals (n = 11) had a baseline glutamate concentration of 1.14 +/- 0.40 mumol/ml (standard error of the mean) before the MCAO. Extracellular glutamate levels increased gradually after vessel occlusion to peak at 10.1 +/- 1.45 mumol/ml 80 minutes after the MCAO. This level gradually decreased to 5.72 +/- 1.67 mumol/ml by 120 minutes. Hypothermic animals (n = 11) had a baseline glutamate concentration of 1.73 +/- 0.83 mumol/ml before the MCAO. Extracellular glutamate levels increased after vessel occlusion but stabilized at 3.47 +/- 1.37 mumol/ml 30 minutes after the MCAO and remained stable until completion of the experiment. There were no significant differences in cortical blood flow between the normothermic and hypothermic groups at any time during the experiment. Infarct volumes, expressed as a percentage of the volume of the right (ipsilateral) hemisphere, were 19.8 +/- 2.16% in the normothermic group and 13.0 +/- 1.42% in the hypothermic group (P < 0.02). Although the normothermic penumbral glutamate levels began to increase immediately after the MCAO, they did not peak until 80 minutes after occlusion. In contrast, the normothermic core glutamate levels peaked within 30 minutes after the MCAO. Glutamate diffusion from the core region to the penumbra might account for this delay. Hypothermic cerebroprotection might involve a reduction in the pool of potentially diffusable glutamate in the core region but have little direct effect on glutamate release in the penumbra.