Up-regulation effect of neureglin1.BETA. on extracellular signal -regulated kinase 5 signaling pathway in rats with cerebral ischemia reperfusion injury

Abstract

Objective To explore the regulating mechanism of neuregulin1β (NRG1β) on extracellular signal-regulated kinase 5 (ERK5) signaling pathway in rats with cerebral ischemia reperfusion injury. Methods Fifty male Wistar rats were divided randomly into sham-operated group, model group, treatment group, inhibitor group, and inhibitor combined with treatment group (n=10). Focal cerebral ischemic models were established by inserting a monofilament thread to achieve middle cerebral artery occlusion (MCAO). The rats were injected 5 μL (2 μg/kg) NRG1β to the internal carotid artery. This inhibitor BIX02189 was injected into the internal carotid artery before ischemia. The neurobehavioral functions were evaluated by modified neurological severity scale (mNSS). The apoptotic cells were counted by terminal deoxynucleotidyl transferase dUTP nick-end labeling, and the expressions of phosphorylated (p-) mitogen activated proteins kinase kinase 5 (MEKK5), ERK5 and myocyte enhancer-binding factor 2C (MEF2C) were determined by immunohistochemical assay and Western blotting. Results The rats in the model group appeared neurobehavioral dysfunction, the number of apoptotic cells in the cortex was increased, and the expressions of p-MEKK5, p-ERK5 and p-MEF2C showed compensable enhancement, which were significantly different as compared with those in the sham-operated group (P<0.05). As compared with those in the model group and inhibitor combined with treatment group, the expressions of p-MEKK5, p-ERK5 and p-MEF2C were further significantly enhanced, the number of apoptotic cells was significantly decreased and the neurobehavioral functions were significantly improved in treatment group (P<0.05). As compared with those in the model group and inhibitor combined with treatment group, the number of apoptotic cells was significantly increased, and the expressions of p-MEKK5, p-ERK5 and p-MEF2C were significantly decreased in the inhibitor group (P<0.05). Conclusion NRG1β could play a neuroprotective role by activating the MEKK5-ERK5-MEF2C signaling pathway and further up-regulating the expressions of p-MEKK5, p-ERK5 and p-MEF2C to inhibit the inflammation induced by cerebral ischemia reperfusion injury in rats. Key words: Neureglin1β; Cerebral ischemia reperfusion injury; Mitogen activated proteins kinase kinase 5; Extracellular signal-regulated protein kinase 5; Myocyte enhancer-binding factor 2