Metformin protects against pericyte apoptosis and promotes neurogenesis through suppressing JNK p38 MAPK signalling activation in ischemia/reperfusion injury

Metformin (MET) has been the subject of many classic studies in possessing antiapoptotic, anti-inflammatory, antioxidation activities and antiviral. Recently investigators have examined the anti-apoptosis effects of MET in acute myocardial infarction and Intracerebral hemorrhage, but very little is currently known about how it regulates ischemic stroke-induced pericytes apoptosis and neural stem cells (NSCs) proliferation. The present research explored the potential neuroprotective mechanisms of MET using transient middle cerebral artery occlusion(tMCAO) mice. The experimental work presented that tMCAO mice treated by metformin had better neurologic outcomes on days 1, 3, and 7 after operation, and alleviated blood-brain barrier (BBB) destruction, brain water content and infarct volume on 72 h after surgery. The data showed that MET alleviated BBB disruption by reducing PDGFR beta/ matrix metalloproteinase-9 (MMP9) positive cells, relieving zonula occludens-1 (ZO-1) drop away and increasing pericyte coverage through remarkably reducing the percentage of PDGFR beta/ caspase-3 positive cells. In addition, MET induced antiapoptotic activity followed by downregulating cleaved caspase-3 and Bax expression. Moreover, JNK signaling pathway has been proved to be pivotal in mediating apoptosis in cerebral ischemia/reperfusion (I/R) injury. The results of this research illustrated that MET treatment downregulated the levels of phosphorylated JNK and P38 in vivo, however the use of JNK activator anisomycin (ANI) could reverse the neuroprotection effect of MET, demonstrating that the JNK pathway is associated with the anti-apoptosis mechanisms of MET. Finally, metformin remarkably increased the percentage of BrdU/DCX-positive cells in subventricular zone (SVZ) and up-regulated BDNF?VEGF and NGF expression after ischemia/reperfusion(I/R) injury on day 7. Our data illustrated that metformin provides an effective therapy for I/R injury.

Automated summary

This study investigated the neuroprotective mechanisms of MET in tMCAO mice and revealed its anti-apoptotic and antioxidation effects. The results showed that MET treatment improved neurological outcomes and reduced blood-brain barrier disruption and infarct volume. Additionally, MET induced anti-apoptotic activity by downregulating cleaved caspase-3 and Bax expression, and inhibited the JNK signaling pathway.