Involvement of MAPK cascade in ischemic neuronal damage

MAPK级联的激活是否会影响亚致死性缺血引起的缺血性神经元损伤和缺血耐受还有待研究。我们获得的证据表明，沙鼠体内短暂性前脑缺血5分钟后，p38在海马体中被激活，抑制p38活性可以防止CA1锥体细胞延迟性神经元死亡。我们还通过Western blot和免疫组织化学证实了沙鼠海马在2分钟亚致死缺血后p38丝分裂原活化蛋白激酶的活化，并且在2分钟缺血前30分钟用活性p38抑制剂SB203580预处理以剂量依赖性方式降低了缺血耐受效应。JNKI还能减轻CA1缺血性损伤。基因破坏p38的靶分子STAT1可减轻小鼠缺血模型中的缺血性损伤。这些发现提示p38可能参与海马CA1神经元的缺血损伤和耐受性，p38级联的组分可能是改变缺血后神经元存活的靶分子。

It remains to be shown whether or not the activations of MAPK cascades may affect ischemic neuronal damage and ischemic tolerance induced by sublethal ischemia. 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 also confirmed the activation of p38 mitogen-activated protein kinase in the gerbil hippocampus by Western blotting and immunohistochemistry after 2 minutes of global sublethal ischemia, and 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.JNKI also attenuated CA1 ischemic damage.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.