Corticotropin-releasing hormone potentiates neural injury induced by oxygen-glucose deprivation: a possible involvement of microglia.
While corticotropin-releasing hormone (CRH) has been implicated in a variety of brain disorders such as ischemic injury, the molecular mechanism by which CRH elicits its activities is largely unclear. In the present study, we have determined the effect of CRH on oxygen-glucose deprivation (OGD) induced apoptosis in fetal hippocampal neurons. CRH alone at concentrations of 10-200 nM had no effect on neuronal apoptosis. However, when neurons were co-cultured with microglia, CRH alone at concentrations greater than 100 nM induced neuronal apoptosis and CRH potentiated significant neuronal apoptosis following exposure to OGD. The effect of CRH on neuronal apoptosis was inhibited in the presence of the CRH antagonist astressin. Real-time RT-PCR revealed an increase in mRNA levels of Fas ligand (Fas-L), a membrane protein related to the TNF family, in cultured microglia following OGD exposure. In the presence of CRH, OGD-induced Fas-L expression was significantly increased. The effect of CRH on Fas-L expression was inhibited by specific inhibitors of the extracellular signal-regulated protein kinase (PD98059) and p38 mitogen-activated protein kinase (SB203580). These results suggest that CRH potentiates neuronal apoptosis induced by OGD in the presence of microglia and that this effect may be mediated through the induction of proinflammatory mediators in microglia.
Wang
Wei
W
Department of Pediatrics, Apps Medical Research Centre, Kingston General Hospital, Queen's University, Doran 3, Room 6-303, Kingston, Ont., Canada K7L 2V7.
Solc
Mark
M
Ji
Ping
P
Dow
Kimberly E
KE
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D003346:Corticotropin-Releasing Hormone; D005947:Glucose