Abstract
BackgroundMetformin, 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.MethodsNinety-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.ResultsInfarct 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.ConclusionsMetformin 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0177-4) contains supplementary material, which is available to authorized users.
Highlights
Metformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials
We showed that mice had significantly lower scores after 3 days in the metformintreated group after transient middle cerebral artery occlusion (tMCAO) for at least 14 days (Figure 2C)
Metformin alleviated neutrophil infiltration and IL-1β, IL-6, TNF-α expression To investigate the effect of metformin on neutrophil infiltration in the acute phase of cerebral ischemia, we performed 3,3’-diaminobenzidine (DAB) staining to detect MPO+ cells
Summary
A widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. Metformin reduces intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) levels in plasma and alleviates chronic inflammation in patients [6]. These effects were independent of its glycemic management properties, suggesting that metformin may have other functions through mechanisms other than glucose reduction. A series of pathological conditions such as glucose deprivation, ischemia, starvation and oxidative stress increase AMPK activity [8]. Agents such as resveratrol and adiponectin can activate AMPK.
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