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Protective and regeneratiove responses endogenously induced in the ischemic brain

缺血脑内源性诱导的保护性和再生反应

基本信息

批准号：
10670585
负责人：
KITAGAWA Kazuo
金额：
$ 1.6万
依托单位：
Osaka 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 1999
项目状态：
已结题

项目摘要

Neuronal cells are highly vulnerable against ischemic insult. Because adult neurons are highly differentiated and they can not be divided by themselves, loss of neurons often result in functional deficit in mammalian brains. However, it has recently been shown that neurons and neuronal circuits exhibit protective and regenerative responses in rodent model of experimental ischemia. We previously found ischemic tolerance phenomenon where sublethal ischemic pretreatment enhances resistance in neurons against subsequent ischemic insult. In the present study, we clarified that small ischemic lesion enhanced neuronal resistance against subsequent ischemia for more than 2 weeks while the effect of ischemic pretreatment usually disappears within 2 weeks. We suggested the involvement of reactive astrocytes in extended neuronal protection. Next, we examined the dynamics of neural stem cells after ischemia in the rat hippocampus using four-vessel occlusion model. Proliferating cells were identified in vivo after i. p. administration of bromodeoxyuridine 1 day before sacrifice. After ischemic insult, the stem cells in the subgranular zone of the dentate gyrus in the hippocampus proliferate at 4 days to 14 days after ischemia and differentiate into the neurons 4 weeks later. Understanding of the molecular mechanism underlying these protective and regenerative responses will be important to develop a new strategy for aiming augmentation of resistance against ischemic insult and replacement of injured neurons.

神经元细胞对缺血性损伤非常脆弱。由于成年神经元高度分化，不能自行分裂，神经元的缺失往往导致哺乳动物脑功能的缺失。然而，最近的研究表明，在啮齿动物实验性缺血模型中，神经元和神经元回路表现出保护和再生反应。我们以前发现缺血耐受现象，即亚致死性缺血预处理增强神经元对随后缺血损伤的抵抗力。在本研究中，我们阐明了小的缺血损伤增强神经元对随后缺血的抵抗力超过2周，而缺血预处理的效果通常在2周内消失。我们建议参与反应性星形胶质细胞在延长神经元保护。接下来，我们使用四血管闭塞模型检测了大鼠海马缺血后神经干细胞的动力学。i. p.在处死前1天施用溴脱氧尿苷。缺血损伤后，海马齿状回颗粒下区的干细胞在缺血后4 ~ 14天增殖，4周后分化为神经元。了解这些保护和再生反应的分子机制将是重要的，以开发一种新的策略，旨在增强对缺血性损伤和更换受损的神经元的抵抗力。