神经调节素1β对脑缺血再灌注损伤ERK5信号通路的调节机制研究  

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

作　　者：李红云[1] 谷宁[1] 季亚清[1] 张睿[1] 郝翠[1] 郭云良[1] 

机构地区：[1]青岛大学附属医院神经科,脑血管病研究所,青岛266003

出　　处：《中华神经医学杂志》2016年第11期1105-1110,共6页Chinese Journal of Neuromedicine

基　　金：山东省科技攻关计划资助项目（2010GWZ20205）

摘　　要：目的探讨神经调节素1β（NRG1β）对脑缺血再灌注损伤后细胞外信号调节激酶5（ERK5）信号通路的调节机制。方法Wistar雄性大鼠50只按照随机数字表法分为假手术组、模型组、治疗组、抑制剂组、抑制剂＋治疗组，每组10只。应用线栓法建立大鼠大脑中动脉缺血再灌注损伤模型，经颈内动脉注射5μL（2μg／kg）NRG1β干预治疗，抑制剂BIX02189于缺血前经颈内动脉注入。采用改良神经功能缺损评分（mNSS）评价大鼠神经功能，采用TUNEL法检测神经细胞凋亡，采用免疫组化染色和Western blotting检测缺血脑组织磷酸化的丝裂原活化蛋白激酶激酶5（MEKK5）、ERK5、肌细胞增强因子2C（MEF2C）表达。结果模型组大鼠表现出神经功能障碍，神经细胞凋亡增多，pMEKK5、pERK5、pMEF2C表达代偿性增强，较假手术组差异均有统计学意义（P〈0．05）。治疗组大鼠pMEKK5、pERK5、pMEF2C表达进一步增强，神经细胞凋亡明显减少，神经功能改善，与模型组和抑制剂＋治疗组比较差异均有统计学意义（P〈0．05）。抑制剂组细胞凋亡增多，pMEKK5、pERK5、pMEF2C蛋白表达显著下降，与模型组和抑制剂＋治疗组比较差异均有统计学意义（P〈0．05）。结论NRG1β可以通过激活MEKK5-ERK5-MEF2C信号通路，进一步上调pMEKK5、pERK5、pMEF2C表达而抑制脑缺血再灌注损伤引起的炎症反应以及神经细胞凋亡，从而发挥神经保护作用。Objective To explore the regulating mechanism ofneuregulin1β （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 ofp-MEKKS, p-ERK5 and p-MEF2C were significantly decreased in the inhibitor group （P〈0.05）. Conclusion NRG1μ could play a

关 键 词：神经调节素1β 脑缺血再灌注损伤 丝裂原活化蛋白激酶激酶5 细胞外信号调节激酶5 肌细胞增强因子2C 

分 类 号：R743[医药卫生—神经病学与精神病学]