PMID- 30387007 OWN - NLM STAT- MEDLINE DCOM- 20200420 LR - 20231213 IS - 1573-675X (Electronic) IS - 1360-8185 (Linking) VI - 24 IP - 1-2 DP - 2019 Feb TI - Sigma-1 receptor protects against endoplasmic reticulum stress-mediated apoptosis in mice with cerebral ischemia/reperfusion injury. PG - 157-167 LID - 10.1007/s10495-018-1495-2 [doi] AB - Reports have showed that Sigma-1 receptor (Sig-1R) activation can protect neurons against cerebral ischemia/reperfusion (I/R) injury in mice and alleviate endoplasmic reticulum (ER) stress in cultured cells, but little known is about the protective role of Sig-1R on ER stress induced by cerebral I/R. The purpose of this study was to determine whether Sig-1R exerts a protective effect against ER stress-mediated apoptosis in cerebral I/R using a 15-min bilateral common carotid artery occlusion (BCCAO) mouse model. At 72 h after reperfusion in BCCAO mice, we found that Sig-1R knockout (Sig-1R KO) significantly increased terminal dUTP nick-end labeling (TUNEL)-positive cells and nuclear structural damage in cortical neurons. Treatment with the Sig-1R agonist PRE084 once daily for three consecutive days reduced the number of TUNEL-positive cells and improved the ultrastructural damage of neurons in the cerebral cortex. These protective effects could be blocked by the Sig-1R antagonist BD1047. Then, we used BCCAO mice at 24 h after reperfusion to detect the expression of ER stress-mediated apoptotic pathway proteins. We found that expression of the pro-apoptotic proteins p-PERK, p-eIF2alpha, ATF, CHOP, p-IRE, p-JNK, Bim, PUMA, cleaved-caspase-12 and cleaved-caspase-3 was significantly increased and that expression of the anti-apoptotic protein Bcl-2 was significantly decreased in Sig-1R KO-BCCAO mice compared with BCCAO mice. Meanwhile, we found that treatment with PRE084 twice a day decreased pro-apoptotic protein expression and increased anti-apoptotic protein expression. The effects of PRE084 were blocked by the Sig-1R antagonist BD1047. These results suggest that Sig-1R activation inhibits ER stress-mediated apoptosis in BCCAO mice, indicating that Sig-1R may be a therapeutic target for neuroprotection particularly relevant to ER stress-induced apoptosis after cerebral I/R injury. FAU - Zhao, Xuemei AU - Zhao X AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. AD - Department of Pharmacology, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar, 161006, People's Republic of China. FAU - Zhu, Lin AU - Zhu L AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. FAU - Liu, Danyang AU - Liu D AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. FAU - Chi, Tianyan AU - Chi T AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. FAU - Ji, Xuefei AU - Ji X AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. FAU - Liu, Peng AU - Liu P AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. FAU - Yang, Xuexue AU - Yang X AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. FAU - Tian, Xinxin AU - Tian X AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. FAU - Zou, Libo AU - Zou L AD - Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China. libozou@163.com. LA - eng GR - 81503057/Research Fund for National Natural Science Foundation of China/International GR - 201601143/Liaoning Province Doctor Startup Fund of the Science and Technology Department of Liaoning Province/International GR - ZQN2015030/Career Development Support Program for Young and Middle-aged Teachers of Shenyang Pharmaceutical University/International GR - 201610163036/Undergraduate Training Programs of Innovation and Entrepreneurship of Shenyang Pharmaceutical University/International PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Netherlands TA - Apoptosis JT - Apoptosis : an international journal on programmed cell death JID - 9712129 RN - 0 (Protective Agents) RN - 0 (Receptors, sigma) SB - IM MH - Animals MH - Apoptosis/*genetics MH - *Brain Ischemia/genetics/metabolism/pathology/prevention & control MH - Cytoprotection/genetics MH - Endoplasmic Reticulum Stress/genetics/*physiology MH - Female MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neurons/physiology MH - Neuroprotection/*genetics MH - Protective Agents/metabolism MH - Receptors, sigma/genetics/*physiology MH - *Reperfusion Injury/genetics/metabolism/pathology/prevention & control MH - Sigma-1 Receptor OTO - NOTNLM OT - Apoptosis OT - ER stress OT - Ischemia/reperfusion OT - Neuron OT - Sigma-1 receptor EDAT- 2018/11/06 06:00 MHDA- 2020/04/21 06:00 CRDT- 2018/11/03 06:00 PHST- 2018/11/06 06:00 [pubmed] PHST- 2020/04/21 06:00 [medline] PHST- 2018/11/03 06:00 [entrez] AID - 10.1007/s10495-018-1495-2 [pii] AID - 10.1007/s10495-018-1495-2 [doi] PST - ppublish SO - Apoptosis. 2019 Feb;24(1-2):157-167. doi: 10.1007/s10495-018-1495-2.