艾司氯胺酮通过调控HMGB1/MAPK轴改善小鼠POCD的机制研究  

Study on the Mechanism of Esketamine to Improve POCD in Mice by Regulating HMGB1/MAPK Axis

作　　者：陶静 梁启胜[1] 薛亚南 张引 李敏[1] 刘磊[1] Tao Jing;Liang Qisheng;Xue Yanan;Zhang Yin;Li Min;Liu Lei(Department of Anesthesiology,the First Affiliated Hospital of Bengbu Medical College,Bengbu 233000 China)

机构地区：[1]蚌埠医学院第一附属医院麻醉科,安徽蚌埠233000

出　　处：《锦州医科大学学报》2023年第6期24-30,共7页Journal of Jinzhou Medical University

基　　金：蚌埠医学院自然科学重点项目,项目编号:2021byzd114。

摘　　要：目的通过观察不同剂量艾司氯胺酮对高迁移率族蛋白1(high mobility group box-1,HMGB1)/丝裂原活化蛋白激酶(mitogen activated protein kinase,MAPK)轴的调控,探究艾司氯胺酮改善小鼠POCD的作用机制。方法选取健康的18个月雄性小鼠随机进行分组,对照组(C组)、脓毒症组(LPS组)、LPS+低剂量艾司氯胺酮组5 mg/kg(LPS+S1)、LPS组+中等剂量艾司氯胺酮组10 mg/kg(LPS+S2)、LPS组+高剂量艾司氯胺酮组15 mg/kg(LPS+S3),LPS+HMGB1抑制剂(LPS+甘草酸组)、LPS+中等剂量艾司氯胺酮干预组+HMGB1抑制剂(LPS+S2+甘草酸组)、LPS+中等剂量艾司氯胺酮干预组+MAPK信号通路抑制剂组(LPS+S2+PD98095组)、LPS+中等剂量艾司氯胺酮干预组+HMGB1抑制剂+MAPK信号通路激活剂(LPS+S2+甘草酸+ANS组)。(艾司氯胺酮干预组是在模型建立后给予第一部分所研究的最佳艾司氯胺酮剂量进行处理)。LPS组是通过腹腔注射LPS 5 mg/kg,HMGB1抑制剂组给予腹腔注射甘草酸剂量为40 mg/kg,对照组注射同等剂量生理盐水。不同药物处理后进行旷场试验和水迷宫实验,之后立即处死小鼠并取其海马组织,采用ELISA测定海马组织白细胞介素-6(interleukin-6,IL-6)、白细胞介素-1(interleukin-1,IL-1)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)。Western Blot检测海马组织HMGB1和MAPK信号通路相关蛋白(p38 MAPK、ERK1/ERK2、JNK)表达水平。结果与对照组小鼠对比,LPS组脓毒症模型小鼠HMGB1、p38 MAPK、ERK1/ERK2、JNK表达增加,差异有统计学意义(P<0.05)。与模型小鼠对比,抑制HMGB1表达后,LPS+S2+甘草酸组脓毒症模型小鼠炎症因子表达降低,差异有统计学意义(P<0.05);与模型小鼠对比,抑制HMGB1表达后,LPS+S2+甘草酸组脓毒症模型小鼠各组小鼠各时点逃避潜伏期时间减少、穿越平台次数增加、总行驶距离增加、中央区域停留时间增加、目标象限时间增加,差异有统计学意义(P<0.05);与模型小鼠对比,抑制MAPK信�Objective By observing the regulation of high mobility group box-1(HMGB1)/mitogen activated protein kinase(MAPK)axis at different doses of esketamine,to explore the mechanism of esketamine improving POCD in mice.Methods Healthy 18-month male mice were randomly divided into different groups:control group(group C),sepsis group(LPS group),and LPS+low-dose esketamine group 5 mg/kg(LPS+S1),LPS+medium-dose esketamine group 10 mg/kg(LPS+S2),LPS+high-dose esketamine group 15 mg/kg(LPS+S3),LPS+HMGB1 inhibitor(LPS+glycyrrhizin group),LPS+medium-dose esketamine intervention group+HMGB1 inhibitor(LPS+S2+glycyrrhizin group),LPS+medium-dose esketamine intervention group+MAPK signaling pathway inhibitor group(LPS+S2+PD98095 group),and LPS+medium-dose esketamine dry Pre-group+HMGB1 inhibitor+MAPK signaling pathway activator(LPS+S2+glycyrrhizic acid+ANS group).The Esketamine intervention group was treated with the optimal dose of Esketamine studied in Part I after the model was established.The LPS group was intraperitoneally injected with LPS 5 mg/kg,the HMGB1 inhibitor group was intraperitoneally injected with glycyrrhizic acid at a dose of 40 mg/kg,and the control group was injected with the same dose of normal saline.Open field test and water maze test were performed after treatment with different drugs,and then the mice were killed immediately and their hippocampal tissues were taken,and the interleukin-6(IL-6),interleukin-1(IL-1)and tumor necrosis factor-α(TNF-α)were determined by ELISA.The expression levels of HMGB1 and MAPK signaling pathway related proteins(p38 MAPK,ERK1/ERK2,JNK)in hippocampus were detected by Western Blot.Results Compared with the control group,the expression of HMGB1,p38 MAPK,ERK1/ERK2 and JNK in the LPS group was increased,and the difference was statistically significant(P<0.05).Compared with the model mice,after inhibiting the expression of HMGB1,the LPS+S2+GA group had a significant reduction in the expression of inflammatory factors(P<0.05);compared with the model mice,after inhibiting the expres

关 键 词：艾司氯胺酮 HMGB1/MAPK轴 脓毒症 炎症因子 旷场试验 水迷宫实验 

分 类 号：R614[医药卫生—麻醉学]