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 PDGFRβ/ matrix
metalloproteinase-9 (MMP9) positive cells, relieving zonula occludens-1
(ZO-1) drop away and increasing pericyte coverage through remarkably
reducing the percentage of PDGFRβ/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.
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