|Budget Amount *help
¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 2000 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1999 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1998 : ¥2,000,000 (Direct Cost : ¥2,000,000)
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.