Sigma-1 receptor in brain ischemia/reperfusion: Possible role in the NR2A-induced pathway to regulate brain-derived neurotrophic factor

摘要

Sigma-1 receptor (sigma 1r) activation could attenuate the learning and memory deficits in the AD model, ischemia model and others. In our previous study, the activation of air increased the expression of brain-derived neurotrophic factor (BDNF), possibly through the NR2A-induced pathway, and sigma 1r agonists might function as neuroprotectant agents in vascular dementia. Here, we used sigma 1r knockout mice to confirm the role of sigma 1r. Furthermore, an antagonist of NR2A was first used to investigate whether the NR2A-induced pathway is the necessary link between sigma 1r and BDNF. The operation of brain ischemia/reperfusion was induced by bilateral common carotid artery occlusion for 20 min in C57BL/6 and al r knockout mice as the ischemic group. A sigma 1r agonist, PRE084 (1 mg/kg, i.p.), and NR2A antagonist, PEAQX (10 mg/kg, i.p.), were administered once daily throughout the experiment. Behavioral tests were performed starting on day 8. On day 22 after brain ischemia/reperfusion, mice were sacrificed and brains were immediately collected and the injured and the hippocampus was isolated and stored at -80 degrees C for western blot analysis. After ischemic operation, contrast with the sigma 1r knockout mice, PRE084 significantly ameliorated learning and memory impairments in the behavioral evaluation, and prevented the protein decline of BDNF, NR2A, CaMKIV and TORC1 expression in wild-type mice. However, the effects of PRE084 on CaMKIV-TORC1-CREB and BDNF, even for learning and memory impairment, were antagonized by the co-administration of PEAQX, an antagonist of NR2A. The activation of air improves the impairment of learning and memory in the ischemia/reperfusion model, and the expression of BDNF, which may have been achieved through the NR2A-CaMKIV-TORC1 pathway. (C) 2017 Published by Elsevier B.V.