脑缺血再灌注损伤(CIRI)是脑卒中的重要病理过程,以神经元细胞死亡和神经功能障碍为特征。二甲双胍,通常用于糖尿病管理,以其神经保护特性而闻名,尽管其对CIRI的影响及其机制尚不清楚。这项研究探讨了二甲双胍对CIRI的神经保护作用,集中于其调节c-JunN末端激酶(JNK)和p38MAP激酶(p38)信号通路的潜力。使用神经元细胞中的氧-葡萄糖剥夺/再灌注(OGD/R)的体外模型和大脑中动脉闭塞(MCAO)的体内小鼠模型,对二甲双胍的疗效进行了评估.用细胞计数试剂盒-8(CCK-8)测量细胞活力,蛋白质表达通过蛋白质印迹(WB),和细胞凋亡通过流式细胞术。使用氯化2,3,5-三苯基四唑(TTC)染色评估小鼠的脑损伤程度,而通过WB和磷酸-JNK(p-JNK)免疫荧光染色检测JNK和p38激活状态。结果显示二甲双胍显著提高了OGD/R后HT22细胞的活力,减少细胞凋亡,并降低了体外OGD/R诱导的JNK和p38的磷酸化。在体内,二甲双胍治疗显著减少MCAO小鼠的脑梗死体积,抑制p-p38和p-JNK表达,增强神经功能.这些结果表明,二甲双胍通过调节JNK/p38信号通路发挥对CIRI的神经保护作用,强调其在治疗脑缺血再灌注损伤方面的潜在治疗价值,为临床应用铺平了道路。
Cerebral ischemia-reperfusion injury (CIRI) is a significant pathological process in stroke, characterized by neuronal cell death and neurological dysfunction. Metformin, commonly used for diabetes management, has been noted for its neuroprotective properties, though its effects on CIRI and the mechanisms involved remain unclear. This study explored the neuroprotective impact of metformin on CIRI, focusing on its potential to modulate the c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38) signaling pathways. Using in vitro models of oxygen-glucose deprivation/reperfusion (OGD/R) in neuronal cells and in vivo mouse models of middle cerebral artery occlusion (MCAO), the effects of metformin were assessed. Cell viability was measured with Cell Counting Kit-8 (CCK-8), protein expression via Western Blot (WB), and apoptosis through flow cytometry. The extent of brain injury in mice was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining, while
JNK and p38 activation statuses were detected through WB and phospho-
JNK (p-
JNK) immunofluorescence staining. Results showed that metformin significantly improved the viability of HT22 cells post-OGD/R, reduced apoptosis, and decreased OGD/R-induced phosphorylation of
JNK and p38 in vitro. In vivo, metformin treatment notably reduced brain infarct volume in MCAO mice, inhibited p-p38 and p-
JNK expression, and enhanced neurological function. These findings suggest that metformin exerts neuroprotective effects against CIRI by modulating the
JNK/p38 signaling pathway, highlighting its potential therapeutic value in treating cerebral ischemia-reperfusion injury and paving the way for clinical applications.