Basic research for cerebral ischemia therapy based on ischemic tolerance

已有研究表明，脑组织预先亚致死性缺血可诱导海马CA 1区对随后致死性缺血应激的缺血耐受现象。我们最近报道了MAPK级联的激活后，管理的3-NP，这是一种线粒体琥珀酸脱氢酶抑制剂，在剂量诱导缺血耐受在沙鼠海马，但它仍有待证明是否激活MAPK级联可能会影响缺血耐受现象引起的亚致死性缺血。在以前的研究中，我们获得的证据表明，p38被激活后5分钟短暂的前脑缺血在体内的沙鼠海马和抑制p38的活性保护对迟发性神经元死亡的CA 1锥体细胞。我们研究了p38丝裂原活化蛋白激酶在沙土鼠海马的激活，通过Western印迹和免疫组织化学来阐明p38激酶在缺血耐受中的作用。免疫印迹分析表明，激活p38在海马后2分钟的全亚致死性缺血。在此2分钟的全脑缺血后，表明活性p38的免疫反应性在再灌注6小时时增强，并在缺血后72小时在CA 1和CA 3神经元中持续显示。在2分钟缺血前30分钟用活性p38抑制剂SB 203580预处理以剂量依赖性方式降低缺血耐受效应。STAT 1（p38的靶向分子）的遗传破坏减少了小鼠缺血模型中的缺血性损伤。这些研究结果表明，p38可能有助于缺血性损伤和耐受性海马CA 1神经元和p38级联的组件可以修改缺血后的神经元存活的靶分子。

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.