Analysis of signal transduction system in ischemic neuronal death

目前已知ERK、p38、JNK属于同一家族，即丝裂原活化蛋白激酶（MAP kinase）。这些激酶被磷酸化级联激活，导致分化、细胞增殖和细胞死亡，如凋亡。特别是，ERK与增殖和生长密切相关，而JNK和p38参与细胞死亡。在目前的研究中，我们调查是否这些激酶参与迟发性神经元死亡在CA 1使用全前脑缺血。通过使用大鼠前脑缺血和免疫印迹法从海马CA1区，齿状回，和皮质获得的样品，我们研究了这些激酶的磷酸化状态，并与组织学结果。在该模型中神经元死亡的CA1区，观察到ERK磷酸化的双相增加，而在其他区域，仅在5分钟时观察到早期增加。诱导缺血耐受后，这种双相增加是最小的。JNK磷酸化在30分钟时仅在CA1和齿状回中短暂观察到。对于p38，只有皮质显示磷酸化增加。这些结果表明，只有持续的磷酸化与缺血性神经元损伤的区域分布全脑缺血。然而，缺血后蛋白质合成明显受到抑制。由于ERK激活转录因子并诱导其他基因，ERK磷酸化是否真的诱导蛋白质诱导神经元死亡仍有待进一步研究。

It is known that ERK, p38, JNK belong to the same family, mitogen-activated protein kinases (MAP kinase). These kinases are activated by a phosphorylation cascade, leading to differentiation, cell proliferation, and cell death such as apoptosis. In particular, ERK is intimately related to proliferation and growth, whereas JNK ad p38 are involved in cell death. In the current study, we investigated whether these kinases are involved in delayed neuronal death in CA1 using global forebrain ischemia. By using rat forebrain ischemia and immunoblotting for samples obtained from hippocampal CA1, dentate gyrus, and cortex, we examined the phosphorylation state of these kinases and correlated with histological outcome. In the CA1 region, where neurons die in this model, biphasic increase of phosphorylation of ERK was observed, whereas in the other regions only early increase at 5 min was noted. Following induction of ischemic tolerance, this biphasic increase was minimal. JNK phosphorylation was transiently observed at 30 min only in CA1 and dentate gyrus. With regard to p38, only cortex showed increased phosphorylation. These results indicate that only persistent phosphorylation was correlated with regional distribution of ischemic neuronal injury following global ischemia. However, protein synthesis is markedly inhibited after ischemia. Since ERK activates transcription factors and induces other genes, whether ERK phosphorylation in fact induces proteins to induce neuronal death remains to be determined by further study.