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The role of intracellular signal transducing system in hypoxia/ischemiainduced brain damage : Therapeutic values of mild hypothermia and drugs

细胞内信号转导系统在缺氧/缺血脑损伤中的作用：亚低温和药物的治疗价值

基本信息

批准号：
03454376
负责人：
SAKABE Takefumi
金额：
$ 3.33万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

The present study was designed to gain further insight into the role of excitonic mechanisms due to overactivity of the neurotransmitters associated with perturbation of intracellular signal transduction may be responsible for brain damage after transient ischemia or hypoxia in rats. 1. Brain ischemia: After transient forebrain ischemia induced by bilateral carotid artery occlusion and hemorrhagic hypotension(BP 50mmHg), the excessive release of DA in striatum due to the increased Ca^<++> influx into presynaptic neurons (opening of the N type Ca channel) was inhibited by the mild hypothermia(-3 ﾟC), staurosporine (protein kinase C inhibitor), and pentobarbital(PB:GABA agonist). By using in vitro autoradiography, the changes of intracellular signal transduction in the hippocampus CA_1 were found during early period of recirculation. The binding sites for^3H-PDBu(protein kinase C) increased while ^3H-forskolin(adenylate cyclase) and ^3H-PN200-110(L type Ca channel) decreased. Mild hypoth … More ermia and PB prevent these perturbations. Ca accumulation in hippocampus CA1 7 days following ischemia were less severe in rats with mild hypothermia, PB, and sadenosyl methionine(SAMe: accelerator of synthesis of phosphatidyl choline). These results suggest that the marked alteration of intracellular signal transduction precedes the delayed neuronal death in the hippocampus CA_1. Memory dysfunction tested by conditioned avoidance response for 7 days after ischemia was also prevented by these treatments.2. Hypoxia: The neurologic disturbances(gait, hypoactivity) and spatial learning deficits were observed after 0.3% CO exposure. The significant decrease of binding sites for ^3H-GTP and ^3H-PN200-110 in hippocampus and cerebral cortex, and ^3H-forskolin and ^3H-PDBu in extrapyramidal system were found 3 and 14 days after CO exposure. These results suggest that perturbation of intracellular signal transduction may be induced in association with neurobehavioral dysfunction in patients with CO intoxication. In conclusion, mild hypothermia and barbiturates ameliorate the excessive neurotransmitter release, derangements of intracellular signal transduction and Ca(i) elevation in the vulnerable brain regions after transient brain hypoxia/ischemia. The GABA agonist, Ca entry blocker, and acceleration of resynthesis of phosphatidyl choline may be beneficial to prevent the delayed neuronal death. Less

本研究旨在进一步了解兴奋性机制的作用，由于过度活动的神经递质与细胞内信号转导的扰动可能是负责短暂缺血或缺氧后的脑损伤大鼠。1.脑缺血：在双侧颈动脉阻断和失血性低血压（BP 50 mmHg）引起的短暂性前脑缺血后，由于突触前神经元Ca^++内流增加（N型Ca通道开放）引起的纹状体DA的过度释放可被亚低温（-3 ℃）、蛋白激酶C抑制剂staurosporine和GABA激动剂戊巴比妥（PB：GABA激动剂）抑制。应用离体放射自显影技术，观察再循环早期海马CA_1区细胞内信号转导的变化。^3 H-PDBu（蛋白激酶C）的结合位点增加，而^3 H-forskolin（腺苷酸环化酶）和^3 H-PN 200 -110（L型钙通道）的结合位点减少。轻度hypoth ...更多信息 ermia和PB防止这些扰动。钙积累在海马CA 1缺血7天后，在大鼠轻度低温，PB，和腺苷蛋氨酸（SAMe：磷脂酰胆碱的合成加速剂）不太严重。结果提示，海马CA_1区迟发性神经元死亡前细胞内信号转导的显著改变。缺血后7天条件性回避反应测试的记忆功能障碍也被这些治疗所预防.缺氧：暴露于0.3%CO后，观察到神经功能障碍（步态、活动减退）和空间学习障碍。CO暴露后3天和14天，海马和大脑皮质中的^3 H-GTP和^3 H-PN 200 -110结合位点以及锥体外系中的^3 H-forskolin和^3 H-PDBu结合位点均显著减少。这些结果表明，细胞内信号转导的干扰可能与CO中毒患者的神经行为功能障碍有关。结论：亚低温和巴比妥类药物可改善短暂性脑缺氧/缺血后易损脑区神经递质的过度释放、细胞内信号转导紊乱和Ca（i）升高。GABA激动剂、Ca内流阻断剂和促进磷脂酰胆碱的再合成可能有助于防止迟发性神经元死亡。少