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

Chang Liu; Di Zhang; Zhengfang Lu; Jiang Man; Zhen Zhang; Xiaojuan Fu; Kefei Cui; Jianping Wang

doi:10.1016/j.neulet.2022.136708

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

Neurosci Lett. 2022 Jul 13:783:136708. doi: 10.1016/j.neulet.2022.136708. Epub 2022 Jun 2.

Authors

Chang Liu¹, Di Zhang², Zhengfang Lu², Jiang Man², Zhen Zhang¹, Xiaojuan Fu¹, Kefei Cui³, Jianping Wang⁴

Affiliations

¹ Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
² Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
³ Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
⁴ Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China. Electronic address: wjpwfy666@126.com.

PMID: 35660649
DOI: 10.1016/j.neulet.2022.136708

Abstract

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.

Keywords: Apoptosis; Blood-brain barrier; Cerebral ischemia/reperfusion injury; JNK signal pathway; Metformin; Neurogenesis; Pericyte.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Brain Ischemia* / metabolism
Caspase 3 / metabolism
Infarction, Middle Cerebral Artery / metabolism
MAP Kinase Signaling System
Metformin* / pharmacology
Mice
Neurogenesis
Pericytes / metabolism
Reperfusion Injury* / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Metformin
p38 Mitogen-Activated Protein Kinases
Caspase 3