Effect of mild hypothermia and hyperthermia on excitatory amino acid-induced brain damage

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Excessive glutamate is lethal to neurons, and the concept of glutamate excitotoxicity has become widely accepted. The purpose of this study was to examine the effects of mild hypothermia and hyperthermia on glutamate excitotoxicity. Glutamate-induced cortical lesions were produced in hypothermic (32℃), normothermic (37℃) and hyperthermic (40℃) rats by perfusion of a 0.5 M glutamate solution via a microdialysis probe. 1) The volume of the lesion 7 days after glutamate perfusion was quantified histologically by image analysis of the lesion. The volume of damage was reduced by mild hypothermia and enlarged by mild hyperthermia. 2) Histological changes in normo- and hypothermic animals were studied using monoclonal antibodies against GFAP (for astrocytes) and ED1 (for macrophages) 0, 1, 3 and 5 days after glutamate perfusion. TUNEL staining was used for evaluation of apoptosis. Mild hypothermia delays macrophage proliferation and apoptosis. 3) In order to examine the effects of mild hypothermia on glutamate-induced NO synthesis, the NO end-products which was observed under the normothermic condition. Both of two No synthase inhibitors (L-NAME, 7-NI) also inhibited the glutamate-induced NO synthesis. 4) We also examined the effect of temperature on the diffusion of exogenously delivered material in the extracellular space using autoradiography of the perfused glutamate solution containing ^<14>C-labeled sucrose. The volume of ^<14>C diffusion also increased as brain temperature increased. These results provide evidence that small variations of brain temperature modify glutamate exicitotoxicity, and that hypothermic neuroprotection is exerted by inhibition of the glutamate-induced NO synthesis. The results also suggest that the change in glutamate diffusion in the extracellular space is one mechanism by which mild hypothermia and hyperthermia exert their protective and harmful effects respectively.