Potential signalling pathways underlying corticotrophin-releasing hormone-mediated neuroprotection from excitotoxicity in rat hippocampus

被引:74
作者
Elliott-Hunt, CR [1 ]
Kazlauskaite, J [1 ]
Wilde, GJC [1 ]
Grammatopoulos, DK [1 ]
Hillhouse, EW [1 ]
机构
[1] Univ Warwick, Dept Biol Sci, Sir Quinton Hazell Mol Med Res Ctr, Coventry CV4 7AL, W Midlands, England
关键词
cAMP; corticotrophin-releasing hormone (CRH); glutamate; hippocampal; mitogen-activating protein kinase (MAPK); neuroprotection;
D O I
10.1046/j.0022-3042.2001.00712.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:416 / 425
页数:10
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