Elliott-Hunt Caroline R, Kazlauskaite Jurate, Wilde Geraint J C, Grammatopoulos Dimitris K, Hillhouse Edward W
Sir Quinton Hazell Molecular Medicine Research Centre, Department of Biological Sciences, University of Warwick, Coventry, UK.
J Neurochem. 2002 Feb;80(3):416-25. doi: 10.1046/j.0022-3042.2001.00712.x.
In several neurological disorders including cerebral ischaemia, glutamate has been implicated as a neurotoxic agent in the mechanisms leading to neuronal cell death. The role of corticotrophin-releasing hormone (CRH), the 41-amino acid peptide, which activates the HPA axis in response to stressful stimuli, remains controversial. In this study, we report that CRH in low physiological concentrations (2 pM), prevented glutamate-induced neurotoxicity via receptor-mediated mechanisms when administered to organotypic hippocampal cultures both during and after the glutamate-induced insult. Detailed investigations on the mechanisms mediating this neuroprotective effect showed that activation of the adenylate cyclase pathway and induction of MAP kinase phosphorylation mediate the CRH action. In addition we showed that CRH can inhibit the phosphorylation of JNK/SAPK by glutamate. Most importantly, we showed that CRH can afford neuroprotection against neurotoxicity up to 12 h following the insult, suggesting that CRH is acting at a late stage in the neuronal death cycle, and this might be important in the development of novel neuroprotective agents in order to improve neuronal survival following the insult.
在包括脑缺血在内的多种神经疾病中，谷氨酸被认为是导致神经元细胞死亡机制中的一种神经毒性剂。促肾上腺皮质激素释放激素（CRH）是一种41个氨基酸的肽，可响应应激刺激激活下丘脑-垂体-肾上腺（HPA）轴，其作用仍存在争议。在本研究中，我们报告称，当在谷氨酸诱导损伤期间及之后给予器官型海马培养物时，低生理浓度（2 pM）的CRH通过受体介导的机制预防了谷氨酸诱导的神经毒性。对介导这种神经保护作用机制的详细研究表明，腺苷酸环化酶途径的激活和丝裂原活化蛋白激酶磷酸化的诱导介导了CRH的作用。此外，我们表明CRH可以抑制谷氨酸诱导的JNK/SAPK磷酸化。最重要的是，我们表明CRH在损伤后长达12小时都能提供针对神经毒性的神经保护作用，这表明CRH在神经元死亡周期的后期起作用，这对于开发新型神经保护剂以提高损伤后神经元的存活率可能很重要。
