| Background and purpose- Metformin is a widely used hypoglycemic drug. Current studies show that metformin could reduce stroke incidence and alleviate chronic inflammation in clinical trials. However, the effect of metformin on ischemic stroke is unclear. Here, we investigated the effect of metformin on mice underwent cerebral ischemia. We further explored the underlying mechanisms.Methods- 120 adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion(t MCAO). Metformin(200mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume(3 days of MCAO) and brain atrophy volume(14 days of MCAO), inflammatory factors, blood brain barrier permeability, angiogenesis, neurogenesis and AMPK signaling pathways were evaluated following t MCAO. In addition, oxygen glucose deprivation was performed on b END.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways.Results- Infarct volume and atrophy volume was greatly reduced in metformin-treated mice compared to the control mice following t MCAO(p<0.05). Neurobehavioral outcomes were also improved in metformin-treated mice(p<0.05). MPO+ cells, MPO activity, and BBB desruption were attenuated after metformin administration(p<0.05). In addition, metformin promotes focal angiogenesis, angiogenesis,activated AMPK and e NOS phosphorylation, \down-regulated cytokines(IL-1b, IL-6, TNF-a) and ICAM-1 expression following t MCAO(p<0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated OGD induced ICAM-1 expression in b END.3 cells(p<0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect.Conclusions- Metformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia induced brain injury by alleviating neutrophil infiltration in acute phase and enhanced neurogenesis and angiogenesis in chronic phase, suggesting that metformin is a promising therapeutic agent in the stroke therapy. |
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