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Sigma–1 receptor activation alleviates blood–brain barrier disruption post cerebral ischemia stroke by stimulating the GDNF–GFRα1–RET pathway
Experimental Neurology ( IF 4.6 ) Pub Date : 2021-09-25 , DOI: 10.1016/j.expneurol.2021.113867
Danyang Liu 1 , Luxi Yang 1 , Peng Liu 1 , Xuefei Ji 1 , Xiaoxiao Qi 1 , Ziqi Wang 1 , Tianyan Chi 2 , Libo Zou 2
Affiliation  

Blood–brain barrier (BBB) disruption is one of the most important pathological manifestations of ischemic stroke. Reducing BBB collapse is effective in alleviating brain parenchymal injury and cognitive dysfunction. Our previous study reported that Sigma–1 receptor (Sig–1R) activation in cerebral microvascular endothelial cells (CMECs) ameliorated BBB impairment, but the detailed mechanism remains unclear. In this study, we investigated Sig–1R activation as a BBB integrity promoter via many post ischemic stroke pathways. Sig–1R activation in BBB–associated astrocytes can increase glia–derived neurotrophic factor (GDNF) secretion in bilateral common carotid artery occlusion (BCCAO) mice. Upregulated GDNF activates its receptors in CMECs to promote BBB integrity, and activated Sig–1R in CMECs facilitates this process. In vitro experiments have found that Sig–1R activation in CMECs promotes the interaction between the GDNF α1 receptor and transduction rearrangement gene, increasing PI3K–AKT–junction protein signaling pathway expression. Sig–1R activation could be an effective therapeutic method for preventing BBB damage in ischemic stroke and other neurological conditions.



中文翻译:


Sigma-1 受体激活通过刺激 GDNF-GFRα1-RET 通路减轻脑缺血性中风后血脑屏障的破坏



血脑屏障(BBB)破坏是缺血性脑卒中最重要的病理表现之一。减少血脑屏障塌陷可有效缓解脑实质损伤和认知功能障碍。我们之前的研究报告称,脑微血管内皮细胞(CMEC)中的Sigma-1受体(Sig-1R)激活可改善BBB损伤,但具体机制仍不清楚。在这项研究中,我们研究了 Sig-1R 通过许多缺血性中风后通路作为血脑屏障完整性促进剂的激活。 BBB 相关星形胶质细胞中的 Sig-1R 激活可以增加双侧颈总动脉闭塞 (BCCAO) 小鼠神经胶质源性神经营养因子 (GDNF) 的分泌。上调的 GDNF 激活 CMEC 中的受体,促进 BBB 完整性,而 CMEC 中激活的 Sig-1R 则促进这一过程。体外实验发现CMECs中Sig-1R的激活促进GDNFα1受体与转导重排基因之间的相互作用,增加PI3K-AKT-连接蛋白信号通路的表达。 Sig-1R 激活可能是预防缺血性中风和其他神经系统疾病中 BBB 损伤的有效治疗方法。

更新日期:2021-09-27
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