Metformin Stimulates Sirtuin1 Expression and Inhibits Ischemic Brain Damage

Abstract

Background and Purpose: Metformin is a well-known medication for type 2 diabetes mellitus. Metformin lowers blood glucose levels, but also activates survival proteins such as sirtiuns in cells. Since sirtuins have a broad range of survival functions like anti-aging, anti-oxidative stress, and longevity, we examined the extent to which metformin possibly via sirtuin activation, reduced ischemic brain damage after metformin treatment.Methods: We induced transient and permanent middle cerebral artery occlusion (MCAO) model in littermate controls and tested the effect of metformin (30 mg/kg, p.o.) on sirtuin expression, as well as the impact of ischemia in brain specific sirtuin overexpressing transgenic (BRASTO) mice. Also, we examined infarction volume and neurological deficit score in BRASTO mice after transient focal cerebral ischemia. PCR was used to confirm BRASTO genotype and western blotting for evaluating protein levels in mice brain tissue lysates.Results: Overall, sirtuins expression decreased following transient focal cerebral ischemia. Sirt1 and Sirt6 were especially reduced. Sirt1 expression in brain lysates was increased by 4 fold compared to WT control in BRASTO mice under basal conditions. Treatment with metformin significantly restored sirtuin levels and this effect appeared independent of reduction in blood glucose levels. Sirt1 expression was significantly increased by 2 fold at 3 hrs following metformin treatment compared to controls. Furthermore infarction volume decreased by 31.5 % and neurological deficit score improved in BRASTO mice suggesting that among the sirtuins, Sirt1 is important following ischemic injury.Conclusions: These results indicate that metformin increases Sirt1 expression in brain during ischemia and the increased Sirt1 may contribute to metformin's neuro-protective and therapeutic benefit in ischemic stroke.