Basic research for cerebral ischemia therapy based on ischemic tolerance

基于缺血耐受的脑缺血治疗基础研究

基本信息

批准号：
15390437
负责人：
NOZAKI Kazuhiko
金额：
$ 9.09万
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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390437/
关键词：
MARK Cerebral ischemia Ischemic tolerance STAT 脳梗塞

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. Genetic disruption of STAT1, a targeted molecule of p38, reduced ischemic damage in a mice ischemic model. These findings suggest that p38 may contribute to both ischemic damage and tolerance in CA1 neurons of the hippocampus and that components of the p38 cascade can be target molecules to modify neuronal survival after ischemia.

据报道，脑组织中先前的唯一缺血诱导了海马CA1区域中随后致死性缺血应激的缺血性耐受性。我们最近报道了在3-np给药后的MAPK级联激活，这是一种线粒体琥珀酸酯脱氢酶抑制剂，该剂量诱导了沙巴氏菌的缺血性耐受性，但仍有待证明MAPK级子的活化是否会影响缺血性宽容的激活，是否会通过缺血性耐受性降低了ISCH的稳固性。在先前的研究中，我们获得了证据表明，在体内5分钟的短暂性前脑缺血后，在沙鼠海马中激活了p38，并且在体内抑制了p38的活性，以防止p38受到CA1锥体细胞的延迟神经元死亡的影响。我们通过蛋白质印迹和免疫组织化学研究了p38有丝分裂原激活蛋白质激酶的激活，以阐明p38激酶在缺血性耐受性中的作用。免疫印迹分析表明，在全球余全缺血2分钟后，海马中p38的激活。经过2分钟的全球性缺血后，在再灌注6小时后增强了活性p38的免疫反应性，并在CA1和CA3神经元中缺血后连续证明。用SB203580预处理是一种活性p38的抑制剂，在2分钟缺血前30分钟以剂量依赖性方式降低了缺血性耐受效应。 STAT1的遗传破坏是p38的靶向分子，减少了小鼠缺血模型的缺血损伤。这些发现表明，p38可能有助于脑缺血损伤和海马CA1神经元的耐受性，并且p38级联反应的成分可以是靶标分子，以修改局部局部局部性神经元存活。