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

本研究旨在进一步了解与细胞内信号转导紊乱相关的神经递质过度活跃所引起的兴奋性机制在大鼠短暂性脑缺血或缺氧后脑损伤中的作用。1.脑缺血：双侧颈总动脉结扎加失血性低血压(BP 50 Mm Hg)所致的短暂性前脑缺血后，亚低温(-3ﾟC)、星形孢菌素(蛋白激酶C抑制剂)和戊巴比妥(PB：GABA激动剂)可抑制因钙离子内流增加而引起的纹状体DA的过度释放(N型钙通道开放)。采用体外放射自显影技术，观察再灌流早期大鼠海马CA1区细胞内信号转导的变化。~(3 H)-PDBu(蛋白激酶C)结合部位增加，~(3 H)-Forsklin(腺苷环化酶)和~(3 H)-PN200-110(L型钙通道)减少。温和假设…更多的ERMIA和PB可以防止这些扰动。亚低温、PB和腺苷蛋氨酸(同为磷脂酰胆碱合成促进剂)组大鼠脑缺血7d后CA1区钙积聚程度较轻。这些结果表明，细胞内信号转导的显著改变先于海马CA_1区神经元的迟发性死亡。用条件性回避反应检测缺血后7天的记忆功能障碍也被这些治疗方法所预防。低氧：0.3%CO暴露后，大鼠出现神经功能障碍(步态、活动减少)和空间学习障碍。CO暴露后3天和14天，海马区和大脑皮层的~(3 H)GTP和~(3 H)-PN200-110结合位点数显著减少，锥体外系的~(3 H)-Forsklin和~(3 H)-PDBu结合位点数显著减少。这些结果提示，CO中毒患者的神经行为功能障碍可能与细胞内信号转导的紊乱有关。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、钙通道阻滞剂和加速磷脂酰胆碱的再合成可能有利于延迟性神经元死亡的预防。较少

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