Xu Qian, Ji Xue-Fei, Chi Tian-Yan, Liu Peng, Jin Ge, Chen Ling, Zou Li-Bo
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
J Neurol Sci. 2017 May 15;376:166-175. doi: 10.1016/j.jns.2017.03.027. Epub 2017 Mar 19.
Sigma-1 receptor (σ1r) activation could attenuate the learning and memory deficits in the AD model, ischemia model and others. In our previous study, the activation of σ1r increased the expression of brain-derived neurotrophic factor (BDNF), possibly through the NR2A-induced pathway, and σ1r agonists might function as neuroprotectant agents in vascular dementia. Here, we used σ1r knockout mice to confirm the role of σ1r. Furthermore, an antagonist of NR2A was first used to investigate whether the NR2A-induced pathway is the necessary link between σ1r and BDNF. The operation of brain ischemia/reperfusion was induced by bilateral common carotid artery occlusion for 20min in C57BL/6 and σ1r knockout mice as the ischemic group. A σ1r agonist, PRE084 (1mg/kg, i.p.), and NR2A antagonist, PEAQX (10mg/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°C for western blot analysis. After ischemic operation, contrast with the σ1r 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 σ1r 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.
σ1受体（σ1r）激活可减轻阿尔茨海默病模型、缺血模型等中的学习和记忆缺陷。在我们之前的研究中，σ1r激活增加了脑源性神经营养因子（BDNF）的表达，可能是通过NR2A诱导的途径，并且σ1r激动剂可能在血管性痴呆中作为神经保护剂发挥作用。在此，我们使用σ1r基因敲除小鼠来证实σ1r的作用。此外，首次使用NR2A拮抗剂来研究NR2A诱导的途径是否是σ1r与BDNF之间的必要联系。将C57BL/6和σ1r基因敲除小鼠作为缺血组，通过双侧颈总动脉闭塞20分钟诱导脑缺血/再灌注手术。在整个实验过程中，每天一次腹腔注射σ1r激动剂PRE084（1mg/kg）和NR2A拮抗剂PEAQX（10mg/kg）。从第8天开始进行行为测试。在脑缺血/再灌注后第22天，处死小鼠并立即收集大脑，分离损伤部位和海马，保存在-80°C用于蛋白质印迹分析。缺血手术后，与σ1r基因敲除小鼠相比，PRE084在行为评估中显著改善了学习和记忆障碍，并防止了野生型小鼠中BDNF、NR2A、CaMKIV和TORC1表达的蛋白质水平下降。然而，NR2A拮抗剂PEAQX的共同给药拮抗了PRE084对CaMKIV-TORC1-CREB和BDNF的作用，甚至对学习和记忆障碍也有拮抗作用。σ1r激活改善了缺血/再灌注模型中的学习和记忆损伤以及BDNF的表达，这可能是通过NR2A-CaMKIV-TORC1途径实现的。
