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Molecular mechanisms of ischemic tolerance in brains

脑缺血耐受的分子机制

基本信息

批准号：
13470292
负责人：
NOZAKI Kazuhiko
金额：
$ 8.9万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

It has been reported that prior sublethal ischemia in brain tissue induces the phenomenon of ischemic tolerance to subsequent lethal ischemic stress in the hippocampal CA1 region. We recently reported the activation of MAPK cascades after the administration of 3-NP, which is a mitochondrial succinate dehydrogenase inhibitor, at a dose that induced ischemic tolerance in the gerbil hippocampus, but it remains to be shown whether or not the activations of MAPK cascades may affect the ischemic tolerance phenomenon induced by sublethal ischemia. In previous studies, we obtained evidence suggesting that p38 was activated in the gerbil hippocampus after 5-minute transient forebrain ischemia in vivo and that the inhibition of the activity of p38 protected against delayed neuronal death in CA1 pyramidal cells. We investigated the activation of p38 mitogen-activated protein kinase in the gerbil hippocampus by Western blotting and immunohistochemistry to clarify the role of p38 kinase in ischemic tolerance. Immunoblot analysis indicated the activation of p38 in the hippocampus after 2 minutes of global sublethal ischemia. After this 2-minute global ischemia, immunoreactivity indicating active p38 was enhanced at 6 hours of reperfusion and continuously demonstrated 72 hours after ischemia in CA1 and CA3 neurons. Pretreatment with SB203580, an inhibitor of active p38, 30 minutes before the 2-minute ischemia reduced the ischemic tolerance effect in a dose-dependent manner. These findings suggest that lasting activation of p38 may contribute to ischemic tolerance in CA1 neurons of the hippocampus and that components of the p38 cascade can be target molecules to modify neuronal survival after ischemia.

已有报道称，脑组织先前的亚致死性缺血可诱导海马CA1区对随后的致死性缺血应激的缺血耐受现象。我们最近报道了线粒体琥珀酸脱氢酶抑制剂3-NP在沙土鼠海马区诱导缺血耐受后MAPK级联的激活，但MAPK级联的激活是否会影响亚致死性缺血诱导的缺血耐受现象尚不清楚。在以前的研究中，我们获得的证据表明，在体短暂性前脑缺血5分钟后，沙土鼠海马区p38被激活，抑制p38活性可以保护CA1锥体细胞免受迟发性神经元死亡。我们通过Western blotting和免疫组织化学方法研究了p38丝裂原活化蛋白激酶在沙土鼠海马区的激活情况，以阐明p38蛋白激酶在脑缺血耐受中的作用。免疫印迹分析显示，在全脑亚致死性缺血2分钟后，海马区p38蛋白被激活。全脑缺血2分钟后，再灌流6小时后，CA1和CA3神经元中p38活性增强，72小时后持续表达。在缺血2min前30min预先给予活性p38抑制剂SB203580，可剂量依赖性地降低缺血耐受效应。这些发现表明，p38的持续激活可能有助于海马区CA1神经元的缺血耐受，并且p38级联的成分可能是改变缺血后神经元存活的靶分子。