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Mechanism of Neuronal Cell Death following Cerebral Ischemia

脑缺血后神经细胞死亡的机制

基本信息

批准号：
05404049
负责人：
KIRINO Takaaki
金额：
$ 21.95万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05404049/
关键词：
Cerebral ischemia Cell daeth Hippocampus Mongolian gerbil Stress protein Protein synthesis Ubiquitin Synapse 免疫染色 cerebral ischemia neuronal death stress response protein synthesis excitotoxin presynaptic terminal ubiqutin

项目摘要

Neurons in the hippocampal CA1 sector die following brief period of ischemia. The neuronal injury here is almost purely postsynaptic. The long term change in remaining presynaptic terminals was studied by fine structural morphometry. The terminals were chronically maintained for longer than 3 months and gradually decreased in number. The CA1 region fell in atrophy in accordance with disappearance of residual presynaptic terminals. Brief ischemia, which in itself is not lethal to hippocampal neurons, confer tolerance to further ischemia even if the ischemic insult is lethal to neurons in intact condition. In neurons which have acquired ischemic tolerance, a stress protein, hsp70, is strongly expressed. We studied the change in protein synthesis in tolerance-induced neurons by autoradiography. Following ischemia, protein synthesis is severely inhibited in Ca1 and never recovers. On the other hand, in tolerance-induced animals, the recovery of protein synthesis was rapid even if ischemia was of lethal level. The change in mRNA for hsp70 was studied by in situ hybridization method. The message was always expressed in CA1 neurons even if the neurons were going to die. Following tolerance induction, mRNA expression was followed by intense expression of hsp70 protein. Another stress-inducible protein, ubiquitin, was known to disappear in CA1 neurons following ischemia. However, this was not the case when we used another type of anti-ubiquitin antibody which recognize mainly conjugated form of ubiquitin. Immunoblot and immunoprecipitation study revealed that uniqutin does not decrease in total amount but free form of ubiquitin is depleted from the CA1 neurons following ischemia. The role of the disappearance of free ubiquitin in ischemic neuronal death is still unknown.

海马CA1区的神经元在短暂的缺血后死亡。这里的神经元损伤几乎是纯粹的突触后损伤。用精细结构形态计量学研究突触前终末的长期变化。终端长期维持超过3个月，数量逐渐减少。CA1区萎缩与残留的突触前终末消失一致。短暂的缺血本身对海马神经元并不致命，即使缺血性损伤对完整状态下的神经元是致命的，它也赋予了对进一步缺血的耐受性。在获得缺血耐受的神经元中，应激蛋白hsp70强烈表达。我们用放射自显影法研究了耐受诱导神经元蛋白质合成的变化。缺血后，Ca1蛋白质合成受到严重抑制，永远不会恢复。另一方面，在耐受诱导的动物中，即使缺血达到致死水平，蛋白质合成的恢复也很快。用原位杂交方法研究热休克蛋白70（hsp70）mRNA的变化。这种信息总是在CA1神经元中表达，即使这些神经元即将死亡。在耐受诱导后，mRNA表达随后是hsp70蛋白的强烈表达。已知另一种应激诱导蛋白泛素在缺血后在CA1神经元中消失。然而，当我们使用另一种类型的主要识别泛素缀合形式的抗泛素抗体时，情况并非如此。免疫印迹和免疫沉淀研究表明，在缺血后，CA1神经元中泛素的总量并不减少，但游离形式的泛素被耗尽。游离泛素的消失在缺血性神经元死亡中的作用尚不清楚。