Mo Shenglong, Yang Chengmin, Zheng Xingwu, Lv Hui, Mao Sanyin, Liu Ning, Yang Qin, Liao Bao, Yang Meiling, Lu Zhicheng, Tang Lina, Huang Xiaorui, Jian Chongdong, Li Xuebin, Shang Jingwei
Department of Neurology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
Biological Molecule Laboratory, Guangxi University Key Laboratory of High Incidence Prevention and Control Research in Western Guangxi, Baise, 53300, Guangxi, China.
Inflammation. 2025 Apr;48(2):713-729. doi: 10.1007/s10753-024-02082-7. Epub 2024 Aug 9.
Following ischemic stroke, aquaporin 4 (AQP4) expression modifications have been associated with increased inflammation. However, the underlying mechanisms are not fully understood. This study aims to elucidate the mechanistic basis of post-cerebral ischemia-reperfusion (I/R) inflammation by employing the AQP4-specific inhibitor, AER-271. The middle cerebral artery occlusion (MCAO) model was used to induce ischemic stroke in mice. C57BL/6 mice were randomly allocated into four groups: sham operation, I/R, AER-271, and 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) treatment, with observations recorded at 1 day, 3 days, and 7 days post-tMCAO. Each group consisted of 15 mice. Procedures included histological examination through HE staining, neurological scoring, Western blot analysis, and immunofluorescence staining. AER-271 treatment yielded significant improvements in post-stroke weight recovery and neurological scores, accompanied by a reduction in cerebral infarction volume. Moreover, AER-271 exhibited a noticeable influence on autophagic and apoptotic pathways, affecting the activation of both pro-inflammatory and anti-inflammatory cytokines. Alterations in the levels of inflammatory biomarkers MCP-1, NLRP3, and caspase 1 were also detected. Finally, a comparative assessment of the effects of AER-271 and TGN-020 in mitigating apoptosis and microglial polarization in ischemic mice revealed neuroprotective effects with no significant difference in efficacy. This study provides essential insights into the neuroprotective mechanisms of AER-271 in cerebral ischemia-reperfusion injury, offering potential clinical applications in the treatment of ischemic cerebrovascular disorders.
缺血性中风后，水通道蛋白4（AQP4）表达的改变与炎症增加有关。然而，其潜在机制尚未完全明确。本研究旨在通过使用AQP4特异性抑制剂AER-271来阐明脑缺血再灌注（I/R）后炎症的机制基础。采用大脑中动脉闭塞（MCAO）模型诱导小鼠缺血性中风。将C57BL/6小鼠随机分为四组：假手术组、I/R组、AER-271治疗组和2-（烟酰胺）-1,3,4-噻二唑（TGN-020）治疗组，在tMCAO术后1天、3天和7天进行观察记录。每组有15只小鼠。实验步骤包括通过苏木精-伊红（HE）染色进行组织学检查、神经功能评分、蛋白质免疫印迹分析和免疫荧光染色。AER-271治疗使中风后体重恢复和神经功能评分有显著改善，同时脑梗死体积减小。此外，AER-271对自噬和凋亡途径有显著影响，影响促炎和抗炎细胞因子的激活。还检测到炎症生物标志物单核细胞趋化蛋白-1（MCP-1）、NLRP3炎性小体和半胱天冬酶-1水平的变化。最后，对AER-271和TGN-020减轻缺血小鼠细胞凋亡和小胶质细胞极化作用的效果进行比较评估，结果显示二者均具有神经保护作用，且疗效无显著差异。本研究为AER-271在脑缺血再灌注损伤中的神经保护机制提供了重要见解，为缺血性脑血管疾病的治疗提供了潜在的临床应用依据。
