Liu Yanqun, Tang Guanghui, Li Yaning, Wang Yang, Chen Xiaoyan, Gu Xiang, Zhang Zhijun, Wang Yongting, Yang Guo-Yuan
Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
J Neuroinflammation. 2014 Oct 15;11:177. doi: 10.1186/s12974-014-0177-4.
Metformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke is unclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further explored the possible underlying mechanisms.
Ninety-eight adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier (BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucose deprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways.
Infarct volume was reduced in metformin-treated mice compared to the control group following tMCAO (P < 0.05). Neurobehavioral outcomes were greatly improved in metformin-treated mice (P < 0.05). MPO+ cells, Gr1+ cells, MPO activity and BBB permeability were decreased after metformin administration (P < 0.05). In addition, metformin activated AMPK phosphorylation, inhibited NF-κB activation, down-regulated cytokine (IL-1β, IL-6, TNF-α) and ICAM-1 expression following tMCAO (P < 0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated oxygen-glucose deprivation-induced ICAM-1 expression in bEND.3 cells (P < 0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect.
Metformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is a promising therapeutic agent in stroke therapy.
二甲双胍是一种广泛使用的降糖药物，在临床试验中可降低中风发病率并减轻慢性炎症。然而，二甲双胍在缺血性中风中的作用尚不清楚。在此，我们研究了二甲双胍对小鼠缺血性中风的影响，并进一步探讨了可能的潜在机制。
98只成年雄性CD-1小鼠接受90分钟的短暂大脑中动脉闭塞（tMCAO）。给予二甲双胍（200mg/kg），持续14天。在tMCAO后评估神经行为学结果、脑梗死体积、炎症因子、血脑屏障（BBB）通透性和AMPK信号通路。对bEND.3细胞进行氧糖剥夺，以探索二甲双胍抑制炎症信号通路的机制。
与对照组相比，tMCAO后二甲双胍治疗的小鼠梗死体积减小（P<0.05）。二甲双胍治疗的小鼠神经行为学结果有显著改善（P<0.05）。给予二甲双胍后，MPO+细胞、Gr1+细胞、MPO活性和BBB通透性降低（P<0.05）。此外，tMCAO后二甲双胍激活AMPK磷酸化，抑制NF-κB激活，下调细胞因子（IL-1β、IL-6、TNF-α）和ICAM-1表达（P<0.05）。此外，二甲双胍激活AMPK信号通路，减轻bEND.3细胞中氧糖剥夺诱导的ICAM-1表达（P<0.05）。选择性AMPK抑制剂Compound C消除了这种促进作用。
二甲双胍以AMPK依赖的方式下调ICAM-1，可通过减轻中性粒细胞浸润有效预防缺血性脑损伤，提示二甲双胍是中风治疗中有前景的治疗药物。
