Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang Province, 161000, China.
Department of Neurosurgery, Qiqihar First Hospital, Qiqihar, Heilongjiang Province, 161000, China.
Cell Biochem Biophys. 2024 Sep;82(3):2597-2606. doi: 10.1007/s12013-024-01373-y. Epub 2024 Jul 24.
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.
脑缺血再灌注损伤（CIRI）是中风的一个重要病理过程，其特征是神经元细胞死亡和神经功能障碍。二甲双胍常用于糖尿病的治疗，其具有神经保护特性已得到证实，但其对 CIRI 的影响及其涉及的机制尚不清楚。本研究探讨了二甲双胍对 CIRI 的神经保护作用，重点研究其对 c-Jun N 端激酶（JNK）和 p38 丝裂原活化蛋白激酶（p38）信号通路的潜在调节作用。使用神经元细胞的氧葡萄糖剥夺/再灌注（OGD/R）体外模型和大脑中动脉闭塞（MCAO）的体内小鼠模型，评估了二甲双胍的作用。通过细胞计数试剂盒-8（CCK-8）测量细胞活力，通过 Western Blot（WB）测量蛋白表达，通过流式细胞术测量细胞凋亡。通过 2,3,5-氯化三苯基四氮唑（TTC）染色评估小鼠脑损伤程度，通过 WB 和磷酸化 JNK（p-JNK）免疫荧光染色检测 JNK 和 p38 的激活状态。结果表明，二甲双胍显著提高了 OGD/R 后 HT22 细胞的活力，减少了细胞凋亡，并降低了体外 OGD/R 诱导的 JNK 和 p38 磷酸化。在体内，二甲双胍治疗明显减少了 MCAO 小鼠的脑梗死体积，抑制了 p-p38 和 p-JNK 的表达，并增强了神经功能。这些发现表明，二甲双胍通过调节 JNK/p38 信号通路对 CIRI 发挥神经保护作用，突出了其在治疗脑缺血再灌注损伤方面的潜在治疗价值，并为临床应用铺平了道路。
