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Mechanism of ischemic neuronal death

缺血性神经元死亡的机制

基本信息

批准号：
01400004
负责人：
KATAOKA Kiyoshi
金额：
$ 10.24万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1991
项目状态：
已结题

项目摘要

We summarize herewith new findings obtained during the threeyear-research project "Mechanism of ischemic neuronal death".1. Delayed neuronal death, selectively occurred in hippocampal CAl area 2-3 days after transient forebrain ischemia, is highly sensitive to cerebral temperature during the insult, and mild hypothermia such as lowering by 4 C almost completely protected neurons from damage. Spontaneous firing of CAl neurons, which totally disappeared during the insult, began to recover along with reperfusion of brain, but the firing frequency decidedly did not exceed the preischemic level ; a fact which is not in accordance with, previous notion that delayed neuronal death is due to postischemic hyperexcitability of CAl neurons.2. Microdialysis studies in gerbil hippocampus coupled with an enzymatic cycling method revealed that forebrain ischemia induced a prompt and hypothermia-sensitive release of glutamate in a large scale (15-20 times preischemic level at 5 min ischemia) followed by a quick return to preischemic range.3. Using gerbil hippocampal slices, we developed a microfluorometry on a fluorescence microscope - a supersensitive video camera - an image analyzer setup. Introducing hypoxiahypoglycemia of perfusion medium induced regionally non-selective glutamate release from whole hippocampal area, within 20 sec of the insult, which followed by regionally selective calcium accumulation in CAl area accompanied by membrane depolarization within 200 sec. Mild hypothermia prolonged the latency in a dose-dependent manner. Taking -together, ischemia induced glutamate release followed by intracellular calcium accumulation is likely to be most crucial in early stage of ischemic neuronal damage.

我们在此总结在为期三年的研究项目“缺血性神经元死亡的机制”1期间获得的新发现。迟发性神经元死亡发生在短暂性前脑缺血后2-3天的海马海马区，对损伤期间的脑温高度敏感，而亚低温(如降低4℃)几乎完全保护神经元免受损伤。损伤后完全消失的CA1神经元自发放电随着脑再灌流而开始恢复，但放电频率明显未超过缺血前水平；这一事实与先前关于迟发性神经元死亡是由于CA1神经元缺血后的高兴奋性有关的观点是不一致的。沙土鼠海马区微透析结合酶循环法研究表明，前脑缺血可引起大量低温敏感的谷氨酸释放(缺血5min时谷氨酸是缺血前水平的15-20倍)，随后迅速恢复到缺血前水平。利用沙土鼠海马片，我们开发了一种在荧光显微镜-超灵敏摄像机-图像分析仪装置上进行显微荧光测量的方法。灌流液中加入低氧低血糖可在20s内引起整个海马区局部非选择性谷氨酸释放，随后在200s内可引起CA1区局部选择性钙积聚并伴有膜去极化。亚低温以剂量依赖的方式延长潜伏期。综上所述，缺血诱导的谷氨酸释放和细胞内钙积聚可能是缺血性神经元损伤早期最关键的环节。