Yuan Ya-Jing, Ye Zhi, Yu Hao, Chen Yang, Wang Yu-Wen, Zhao Jun-Hua, Sun Ji-Feng, Xu Li-Ming
Department of Anesthesia, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, P.R. China.
Department of Anesthesia, The Affiliated Xiangya Hospital of Center South University, Changsha, P.R. China.
FASEB J. 2020 Dec;34(12):15837-15848. doi: 10.1096/fj.202000458RR. Epub 2020 Oct 20.
Acute ischemic stroke is one of the leading causes of death in developed countries and the most common cause of disability in adults worldwide. Despite advances in the understanding of stroke pathophysiology, therapeutic options remain limited. In this study, we explored the interaction of Shrm4 and the metabotropic gamma-aminobutyric acid (GABA) receptors (GABA ) in ischemic stroke. A transient middle cerebral artery occlusion (MCAO) model was induced by filament insertion in Shrm4+/+ and wild-type C57BL/6J mice, followed by reperfusion for up to 7 days. Baclofen was administered was used to activate GABA in vivo during reperfusion. Neurological deficits, motor and memory functions, and infarct volume were determined in the various mouse groups. Furthermore, we also developed an oxygen-glucose deprivation (OGD) cell model in primary neurons to test Shrm4/GABA interactions in vitro. Shrm4 was observed to decrease infarct volume and neuronal cell loss in penumbra, and rescue neurological deficits in MCAO mice. Notably, Shrm4 also increased pole climbing speed, reduced foot faults, and increased escape latency in the Morris water maze test, while reducing neuron autophagy through an interaction with GABA receptors. GABA activation using baclofen further reduced OGD-induced neuron damage in culture and stroke outcomes of MCAO, relative to Shrm4 alone. Taken together, Shrm4-mediated GABA activation confers neuroprotection by reducing neuronal autophagy in acute ischemic stroke.
急性缺血性中风是发达国家主要的死亡原因之一，也是全球成年人残疾的最常见原因。尽管在中风病理生理学的理解方面取得了进展，但治疗选择仍然有限。在本研究中，我们探讨了Shrm4与代谢型γ-氨基丁酸（GABA）受体（GABA ）在缺血性中风中的相互作用。通过将细丝插入Shrm4+/+和野生型C57BL/6J小鼠中诱导短暂性大脑中动脉闭塞（MCAO）模型，然后再灌注长达7天。在再灌注期间给予巴氯芬以在体内激活GABA。测定了各个小鼠组的神经功能缺损、运动和记忆功能以及梗死体积。此外，我们还在原代神经元中建立了氧-葡萄糖剥夺（OGD）细胞模型，以在体外测试Shrm4/GABA的相互作用。观察到Shrm4可减少梗死体积和半暗带中的神经元细胞损失，并挽救MCAO小鼠的神经功能缺损。值得注意的是，在莫里斯水迷宫试验中，Shrm4还提高了爬杆速度，减少了足部失误，并增加了逃避潜伏期，同时通过与GABA受体的相互作用减少了神经元自噬。相对于单独使用Shrm4，使用巴氯芬激活GABA进一步减少了培养物中OGD诱导的神经元损伤以及MCAO的中风结局。综上所述，Shrm4介导的GABA激活通过减少急性缺血性中风中的神经元自噬而赋予神经保护作用。
