Analysis of signal transduction system in ischemic neuronal death

缺血性神经元死亡的信号转导系统分析

基本信息

批准号：
10671284
负责人：
KAWAHARA Nobutaka
金额：
$ 2.24万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671284/
关键词：
MAP kinase Cerebral ischemia Delayed neuronal death apoptosis protein phosphorylation

项目摘要

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.

众所周知，ERK，p38，JNK属于同一家族，有丝分裂原激活的蛋白激酶（MAP激酶）。这些激酶通过磷酸化级联反应激活，导致分化，细胞增殖和细胞死亡（例如凋亡）。特别是，ERK与增殖和生长密切相关，而JNK AD P38参与细胞死亡。在当前的研究中，我们研究了这些激酶是否使用全球前脑缺血参与CA1中的神经元死亡。通过使用大鼠前脑缺血和免疫印迹，用于从海马CA1，齿状回和皮层获得的样品，我们检查了这些激酶的磷酸化态，并与组织学结果相关。在该模型中神经元死亡的CA1区域中，观察到ERK磷酸化的双相增加，而在其他区域则仅在5分钟时才提早增加了ERK的磷酸化。诱导缺血性耐受性后，这种双相增加是最小的。 JNK磷酸化仅在30分钟的CA1和齿状回中瞬时观察到。关于p38，仅皮层显示磷酸化增加。这些结果表明，仅持续的磷酸化与全球缺血后缺血性神经元损伤的区域分布相关。然而，缺血后明显抑制蛋白质的合成。由于ERK激活转录因子并诱导其他基因，因此ERK磷酸化实际上是否诱导蛋白质诱导神经元死亡仍有待进一步研究尚待确定。