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

亚低温和高温对兴奋性氨基酸所致脑损伤的影响

基本信息

批准号：
10671305
负责人：
FUJISAWA Hirosuke
金额：
$ 1.73万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2001
项目状态：
已结题

项目摘要

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.

过量的谷氨酸对神经元是致命的，谷氨酸兴奋毒性的概念已被广泛接受。本研究的目的是研究亚低温和高温对谷氨酸兴奋毒性的影响。通过微透析探针灌注0.5M谷氨酸溶液，在低温（32℃）、常温（37℃）和高温（40℃）大鼠中产生谷氨酸诱导的皮层损伤。1)谷氨酸灌注后7天的病变体积通过病变的图像分析进行组织学定量。亚低温可使损伤体积减小，亚高温可使损伤体积增大。2)在常温和低温动物的组织学变化进行了研究，使用单克隆抗体对GFAP（星形胶质细胞）和ED 1（巨噬细胞）0，1，3和5天后，谷氨酸灌注。TUNEL法检测细胞凋亡。亚低温延缓巨噬细胞增殖和凋亡。3)为了研究亚低温对谷氨酸诱导的NO合成的影响，在常温条件下观察了NO终末产物。两种NO合成酶抑制剂（L-NAME、7-NI）也能抑制谷氨酸诱导的NO合成。4)我们还研究了温度对外源性物质在细胞外空间中扩散的影响，使用含有13 C标记蔗糖的灌注谷氨酸溶液的放射自显影<14>。^<14>C扩散量也随脑温升高而增加。这些结果提供的证据表明，大脑温度的小变化修改谷氨酸兴奋毒性，低温神经保护是通过抑制谷氨酸诱导的NO合成。结果还表明，谷氨酸在细胞外空间扩散的变化是一种机制，亚低温和高温分别发挥其保护和有害的影响。