NRG-1β Exerts Neuroprotective Effects Against Ischemia Reperfusion-induced Injury In Rats Through JNK Signaling Pathway

Background: The aim of the current study was to analyze the effects and possible signaling pathway of neuregulin1β(NRG1β)on brain tissues in a rat model of middle cerebral artery occlusion/reperfusion(MCAO/R).Methods: The experimental rats were randomly divided into sham group,model group,SP600125(positive control)group,NRG1β(treatment)group,SP600125+NRG1β group and vehicle group.In order to observe the protective effect of NRG1β on MCAO/R,the neurological deficit and infarct volume were measured using a modified neurological severity score(m NSS)test and by triphenyl tetrazolium chloride(TTC)staining.In order to detect the antagonistic effect of NRG1β on nerve cells and the blood brain barrier(BBB),the morphology and structure of cortical brain tissues were observed by hematoxylin-eosin(H&E)and Nissl staining,transmission electron microscopy(TEM),and in situ cell death detection kit.In order to detect the protective effect of NRG1β on the blood brain barrier(BBB),the integrity of the BBB was observed by Evans Blue(EB)staining.In order to investigate whether NRG1β exhibited a significant neuroprotective effect via the JNK signaling pathway,the levels of phospho-MKK4,phospho-JNK,pan-JNK and phospho-c-Jun and the activity of JNK were tested using immunohistochemical,immunofluorescent labeling,western blot analysis,and a JNK activity screening kit,respectively.Results: In the current study,we observed that along with an increase in JNK activity after MCAO/R,neurological severity score and brain infarct volume were significantly increased,the pathology and ultra-structure changes of brain cells and neurons were obvious,the integrity of the BBB was damaged,and the protein levels of phospho-JNK,phospho-MKK4 and phospho-c-Jun in rat brains was increased(P<0.05).In the NRG1βtreatment group,accompanied with a decrease in JNK activity,the protein levels of phospho-JNK,phospho-MKK4 and phospho-c-Jun decreased,the integrity of the BBB was restored,the ischemia-induced apoptosis decreased,the abnormal morphological structures of nerve cells were ameliorated,and infarct volume was reduced.At the same time,neurological function was significantly recovered(P<0.05).Conclusion: NRG1β exerts a neuroprotective effect through the JNK signaling pathway in MCAO/R rats.