Sigma-1 Receptor Improves The Impairments Of Learning And Memory Induced By Brain Ischemia/reperfusion Based On Neurotrophic Factors

ObjectivesSigma-1 receptor(Sig-IR)agonists showed anti-amnesic properties-in Alzheimer's disease models and anti-inflammatory properties in cerebral ischemia models,however,the effects of Sig-1R activation on learning and memory impairment in vascular dementia are still uncertain.The agonist of Sig-1R was reported to up-regulate brain-derived neurotrophic factor(BDNF)levels in the hippocampus of rats.Here,we investigated whether the activation of Sig-1R attenuates the learning and memory impairment induced by ischemia/reperfusion and how it affects the expression of BDNF.Materials and methodsBilateral common carotid artery occlusion(BCCAO)was performed for 20 minutes in C57BL/6 mice and Sig-1R knockout mice.Sig-1R agonist,PRE084,sigma 1/2 non-selective agonist,DTG,Sig-1R antagonist,BD1047 and NMDA receptor 2A(NR2A)antagonist,PEAQX,were injected intraperitoneally once daily throughout the experiment.Behavioural tests were performed from day 8.On day 22 after BCCAO,mice were sacrificed for molecular biological analysis.Results(1)In C57BL/6 mice,Sig-1R agonist PRE084 and sigma 1/2 non-selective agonist DTG ameliorated learning and memory impairments induced by BCCAO in the Y maze,novel object recognition and water maze tasks,meanwhile,Sig-1R antagonist,BD1047 blocked the improvement effects of PRE084 and DTG.PRE084 didn't ameliorate the learning and memory impairments in Sig-1R knockout mice after BCCAO.(2)BCCAO induced the loss of neurons and synaptic proteins,and the decline of BDNF,phosphorylation of TrkB and ERK expression in the hippocampus.PRE084 and DTG prevented the decline of above proteins in BCCAO mice.After co-administration of BD1047,the effects of PRE084 and DTG were antagonized.PRE084 did not improve the expression of BDNF in Sig-1R knockout mice.(3)The level of NR2A,calcium/calmodulin-dependent protein kinase type ?(CaMKIV)and CREB-specific co-activator transducer of regulated CREB activity 1(TORC1)decreased after BCCAO,however,PRE084 and DTG up-regulated these proteins expression in BCCAO mice.The effects of PRE084 and DTG were antagonized by the co-administration of BD1047.The effects of PRE084 on these proteins disappeared in Sig-1R knockout mice.(4)The effects of PRE084 on the CaMKIV-TORC1-CREB and BDNF,even on the learning and memory impairments,were antagonized by co-administration of NR2A antagonist PEAQX.(5)PRE084 and DTG showed no effects on the expression of NT-3,CNTF,bFGF and VEGF.Conclusions1.Sig-1R activation could significantly attenuate the learning and memory impairment and the loss of neurons and synaptic proteins in the ischemia/reperfusion mice model.2.The activation of Sig-1R could increase the expression of BDNF,but no influences were found in the expression of NT-3,CNTF,bFGF and VEGF.3.Sig-1R activation could regulate BDNF expression through the NR2A-CaMKIV--TORC1 pathway.Sig-1R agonists might function as neuroprotective agents in vascular dementia.