EGB761改善缺血性脑卒中模型小鼠的认知功能障碍并降低小胶质细胞激活  

EGB761 ameliorates cognitive dysfunction and attenuates microglial activation in a mouse model of ischemic stroke

作　　者：王华[1] 张驰 张小广[1,3] WANG Hua;ZHANG Chi;ZHANG Xiao-guang(Dept of Neurology,the First Affiliated Hospital of Henan University,Kaifeng Henan 475000,China;School of Basic Medicine and Forensic Medicine,Henan University of Science and Technology,Luoyang,Henan 471000,China;Dept of Neurosurgery,the First Affiliated Hospital of Henan University,Kaifeng Henan 475000,China)

机构地区：[1]河南大学第一附属医院神经内科,河南开封475000 [2]河南科技大学基础医学与法医学院,河南洛阳471000 [3]河南大学第一附属医院神经外科,河南开封475000

出　　处：《中国药理学通报》2024年第10期1872-1878,共7页Chinese Pharmacological Bulletin

基　　金：河南省医学科技攻关计划联合共建项目(LHGJ20220650)。

摘　　要：目的探讨EGB761对缺血性脑卒中后小鼠的认知功能障碍的改善作用及相关机制。方法将72只小鼠随机均分为4组(n=18):假手术组、模型组、低和高剂量EGB761治疗组。利用线栓法构建大脑中动脉闭塞/再灌注(MCAO/R)小鼠模型,其中低和高剂量EGB761组于MCAO/R术后分别给予50 mg·kg^(-1)和150 mg·kg^(-1)EGB761,每天1次,持续28天。TTC染色测量脑梗死体积;用改良神经功能评分(mNSS)表评估小鼠神经功能;水迷宫实验评估小鼠的学习认知功能;NeuN和TUNEL共染色检测神经元凋亡;Iba1免疫荧光染色评估小胶质细胞激活情况;Western blot检测TLR4、p-IKKɑ和NF-κB蛋白的表达水平。结果与模型组相比,低和高剂量EGB761组小鼠的脑梗死体积明显缩小(P<0.01),神经功能及学习认知功能明显改善(P<0.01),凋亡神经元百分比明显降低(P<0.01),小胶质细胞活化(P<0.01),TLR4、p-IKKɑ和NF-κB表达明显下降(P<0.05)。高剂量治疗组比低剂量治疗组疗效明显。结论EGB761可改善MACO/R小鼠的神经功能障碍和认知功能障碍,其机制可能与降低神经元凋亡,并可抑制TLR4/NF-κB通路减少小胶质细胞的过度激活有关。Aim To investigate the effect of EGB761 on cognitive impairment in mice following ischemic stroke and its underlying mechanism.Methods Seventy-two mice were randomly divided into four groups(n=18 each):sham group,model group,low-dose EGB761 treatment group,and high-dose EGB761 treatment group.The middle cerebral artery occlusion/reperfusion(MCAO/R)mouse model was established using the thread occlusion method.The low-and high-dose groups received 50 mg·kg^(-1)and 150 mg·kg^(-1)of EGB761 respectively,once daily for 28 days after MCAO/R.Cerebral infarction volume was measured using TTC staining.Neurological function was evaluated using the modified neurological function score(mNSS).The learning and cognitive function of mice was assessed by the water maze test.Neuronal apoptosis was detected through NeuN and TUNEL co-staining.Iba1 immunofluorescence staining was used to evaluate microglia activation.The protein expression levels of TLR4,p-IKKɑand NF-κB were detected by Western blot.Results Compared with the model group,both low-dose and high-dose EGB761 groups exhibited a significant reduction in cerebral infarction volume(P<0.01),improvement in neurological function as well as learning and cognitive function(P<0.01),a significant decrease in apoptotic neurons percentage(P<0.01),along with activated microglia(P<0.01).Furthermore,expressions of TLR4,p-IKKɑand NF-κB were significantly reduced(P<0.05).Notably,the high-dose treatment demonstrated more pronounced effects than the low-dose treatment did.Conclusion EGB761 can ameliorate neurological and cognitive dysfunction in MACO/R mice by reducing neuronal apoptosis while inhibiting the TLR4/NF-κB pathway to mitigate excessive activation of microglia.

关 键 词：EGB761 缺血性脑卒中 小鼠 认知功能障碍 神经元 小胶质细胞 TLR4/NF-κB通路 

分 类 号：R-332[医药卫生] R284.1R322.81R329.25R338.64R743.31