Metformin is a first-line anti-diabetic agent with a powerful
hypoglycemic effect. Several studies have reported that
metformin can improve the prognosis of
stroke patients and that this effect is independent of its
hypoglycemic effect; however, the specific mechanism remains unclear. In this research, we explored the effect and specific mechanism of
metformin in
cerebral ischemia-reperfusion (I/R) injury by constructing a transient
middle cerebral artery occlusion model in vivo and a
glucose and
oxygen deprivation/reoxygenation (OGD/R) model in vitro. The results of the in vivo experiments showed that acute treatment with low-dose
metformin (10 mg/kg) ameliorated
cerebral edema, reduced the
cerebral infarction volume, improved the neurological deficit score, and ameliorated neuronal apoptosis in the ischemic penumbra. Moreover,
metformin up-regulated the
brain-derived neurotrophic factor (
BDNF) expression and increased phosphorylation levels of
AMP-activated protein kinase (AMPK) and
cAMP-response element binding protein (CREB) in the
ischemia penumbra. Nevertheless, the above-mentioned effects of
metformin were reversed by Compound C. The results of the in vitro experiments showed that low
metformin concentrations (20 μM) could reduce apoptosis of human umbilical vein endothelial cells (HUVECs) under OGD/R conditions and promote cell proliferation. Moreover,
metformin could further promote
BDNF expression and release in HUVECs under OGD/R conditions via the AMPK/CREB pathway. The Transwell chamber assay showed that HUVECs treated with
metformin could reduce apoptosis of SH-SY5Y cells under OGD/R conditions and this effect could be partially reversed by transfection of
BDNF siRNA in HUVECs. In summary, our results suggest that
metformin upregulates the level of
BDNF in the cerebral ischemic penumbra via the AMPK/CREB pathway, thereby playing a protective effect in cerebral I/R injury.