Zheng Xiaolong, Yang Jun, Zhu Zhou, Fang Yongkang, Tian Yeye, Xie Minjie, Wang Wei, Liu Yang
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Mol Neurobiol. 2022 Apr;59(4):2305-2327. doi: 10.1007/s12035-021-02702-5. Epub 2022 Jan 24.
Earlier studies have shown the neuroprotective role of TWIK-related K channel 1 (TREK-1) in global cerebral and spinal cord ischemia, while its function in focal cerebral ischemia has long been debated. This study used TREK-1-deficient mice to directly investigate the role of TREK-1 after focal cerebral ischemia. First, immunofluorescence assays in the mouse cerebral cortex indicated that TREK-1 expression was mostly abundant in astrocytes, neurons, and oligodendrocyte precursor cells but was low in myelinating oligodendrocytes, microglia, or endothelial cells. TREK-1 deficiency did not affect brain weight and morphology or the number of neurons, astrocytes, or microglia but did increase glial fibrillary acidic protein (GFAP) expression in astrocytes of the cerebral cortex. The anatomy of the major cerebral vasculature, number and structure of brain micro blood vessels, and blood-brain barrier integrity were unaltered. Next, mice underwent 60 min of focal cerebral ischemia and 72 h of reperfusion induced by the intraluminal suture method. TREK-1-deficient mice showed less neuronal death, smaller infarction size, milder blood-brain barrier (BBB) breakdown, reduced immune cell invasion, and better neurological function. Finally, the specific pharmacological inhibition of TREK-1 also decreased infarction size and improved neurological function. These results demonstrated that TREK-1 might play a detrimental rather than beneficial role in focal cerebral ischemia, and inhibition of TREK-1 would be a strategy to treat ischemic stroke in the clinic.
早期研究表明，TWIK相关钾通道1（TREK-1）在全脑和脊髓缺血中具有神经保护作用，而其在局灶性脑缺血中的功能长期以来一直存在争议。本研究使用TREK-1基因敲除小鼠直接探究TREK-1在局灶性脑缺血后的作用。首先，对小鼠大脑皮层进行免疫荧光分析表明，TREK-1在星形胶质细胞、神经元和少突胶质前体细胞中表达最为丰富，而在有髓少突胶质细胞、小胶质细胞或内皮细胞中表达较低。TREK-1基因敲除不影响脑重量、形态或神经元、星形胶质细胞或小胶质细胞的数量，但确实增加了大脑皮层星形胶质细胞中胶质纤维酸性蛋白（GFAP）的表达。大脑主要血管的解剖结构、脑微血管的数量和结构以及血脑屏障的完整性均未改变。接下来，采用管腔内缝合法对小鼠进行60分钟的局灶性脑缺血和72小时的再灌注。TREK-1基因敲除小鼠的神经元死亡较少、梗死面积较小、血脑屏障（BBB）破坏较轻、免疫细胞浸润减少且神经功能较好。最后，对TREK-1进行特异性药理抑制也减小了梗死面积并改善了神经功能。这些结果表明，TREK-1在局灶性脑缺血中可能起有害而非有益的作用，抑制TREK-1可能是临床上治疗缺血性中风的一种策略。
