Sigma 1 receptor activation regulates brain-derived neurotrophic factor through NR2A-CaMKIV-TORC1 pathway to rescue the impairment of learning and memory induced by brain ischaemia/reperfusion.

Abstract

Sigma-1 receptor (Sig-1R) agonists showed anti-amnesic properties in Alzheimer's disease models and anti-inflammatory properties in cerebrum ischaemia models. The agonist of Sig-1R was reported to up-regulate brain-derived neurotrophic factor (BDNF) levels in the hippocampus of mice. Here, we investigate whether the activation of Sig-1R attenuates the learning and memory impairment induced by ischaemia/reperfusion and how it affects the expression of BDNF. Bilateral common carotid artery occlusion (BCCAO) was induced for 20 min in C57BL/6 mice. Sig-1R agonist, PRE084, sigma 1/2 non-selective agonist, DTG, Sig-1R antagonist and BD1047 were injected once daily throughout the experiment. Behavioural tests were performed from day 8. On day 22 after BCCAO, mice were sacrificed for biochemical analysis. PRE084 and DTG ameliorated learning and memory impairments in the Y maze, novel object recognition, and water maze tasks and prevented the decline of synaptic proteins and BDNF expression in the hippocampus of BCCAO mice. Furthermore, PRE084 and DTG up-regulated the level of NMDA receptor 2A (NR2A), calcium/calmodulin-dependent protein kinase type IV (CaMKIV) and CREB-specific co-activator transducer of regulated CREB activity 1 (TORC1). Additionally, the effects of PRE084 and DTG were antagonised by the co-administration of BD1047. Sig-1R activation showed an attenuation in the ischaemia/reperfusion model and the activation of Sig-1R increased the expression of BDNF, possibly through the NR2A-CaMKIV-TORC1 pathway, and Sig-1R agonists might function as neuroprotectant agents in vascular dementia.