Two different molecular mechanisms underlying progesterone neuroprotection against ischemic brain damage

作     者：Cai, W. Y. Zhu, Y. Furuya, K. Li, Z. Sokabe, M. Chen, L. Nanjing Med Univ, Lab Reprod Med, Dept Physiol, Nanjing 210029, Jiangsu, Peoples R China. Nagoya Univ, Grad Sch Med, Dept Physiol, Nagoya, Aichi 4668550, Japan. JST, ICORP SORST Cell Mechanosensing, Nagoya, Aichi 4668550, Japan. Natl Inst Physiol Sci, Dept Mol Physiol, Okazaki, Aichi 4448585, Japan. 

出 版 物：《南京医科大学学报(自然科学版)》 (Journal of Nanjing Medical University(Natural Sciences))

年 卷 期：2008年第10期

页      面：1355-1355页

学科分类：1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

主　　题：progesterone(P4) middle cerebral artery occlusion(MCAO) extracellular receptor kinase(ERK) NMDA receptor (NMDAr) sigma1 (sigma (1) ) receptor cerebral-artery occlusion long-term potentiation methyl-d-aspartate preconditioning-induced activation cerebellar purkinje-cells hippocampal ca1 region rat hippocampus protein-kinase nmda receptor tyrosine phosphorylation 

摘      要：Herein, we show that a single injection of P4(4 mg/kg) at 1 h or 48 h, but not 96 h, before middle cerebral artery occlusion (MCAO) produces significant protective effects against the ischemia-induced neuronal death and the deficits in spatial cognition and UP induction. The present study focused on the molecular mechanisms underlying the neuroprotection exerted by P4 administration at I h and 48 h pre-MCAO, termed acute and delayed P4-neuroprotection, respectively. Pharmacology suggested that P4-receptor(P4R) cascading to a Src-ERK1/2 signaling mediated the delayed P4-neuroprotection. To support this, it was observed by anti-phosph-ERK1/2 immunoblots that a single injection of P4 triggered a P4R-mediated persistent increase in ERK1/2 phosphorylation and their nuclear translocation for 48 h. In contrast, the acute P4-neuroprotection did not depend on the P4R-mediated Src-ERK1/2 signaling. Instead, the acute P4-administration attenuated the NMDA-induced rise in the intracellular calcium concentration([Ca2+] (i) ) that may be a primary cause for MCAO-induced neuronal injury. This effect seemed to be exerted by an antagonism of sigma(1) receptor since the sigma(1) receptor antagonist NE100 perfectly mimicked the acute P4-neuroprotection and also attenuated the NM- DA-incluced [Ca2+] (i), increase. These findings suggest that the P4 neuroprotection involves two independent processes depending on the timing of P4 administration before MCAO: an acute protection by antagonizing sigma (1) receptor to inhibit NMDAr-Ca2+ influx and a delayed one by an activation of P4R-mediated SrcERK signaling pathway. (C) 2008 Elsevier Ltd. All rights reserved.