右美托咪定对脓毒症小鼠中枢神经炎症反应的调控及机制研究

A Study on Regulation and Mechanism of Dexmedetomidine on Central Nervous Inflammatory Response in Septic Mice

目的探究右美托咪定(Dex)通过减轻脓毒症小鼠外周和大脑海马区神经炎症反应对神经认知功能恢复的影响。方法选择51只CD1小鼠随机分为假手术组、脓毒症组、Dex组各17只。假手术组小鼠仅行开腹手术及盲肠暴露操作,余下2组采用盲肠结扎及穿孔的方式建立脓毒症小鼠模型,建模成功后,Dex组小鼠采用Dex腹腔注射,而假手术组、脓毒症小鼠于相同时间予生理盐水腹腔注射。观察各组小鼠1、2、3、4 d学习记忆能力(进入目标盒时间)及不同条件恐惧实验僵直时间,比较各组小鼠大脑海马区高迁移率族蛋白1(HMGB1)、晚期糖基化终末产物受体(RAGE)、Iba-1、伊文氏蓝(EB)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)水平及外周血TNF-α、IL-6、IL-1β水平。结果1、2、3、4 d时,脓毒症组小鼠进入目标盒时间显著长于假手术组,Dex组小鼠进入目标盒时间显著短于脓毒症组(P<0.05)。在环境及声音条件恐惧实验中,脓毒症组小鼠僵直时间均显著短于假手术组,Dex组小鼠僵直时间均显著长于脓毒症组(P<0.05)。脓毒症组小鼠大脑海马区HMGB1、RAGE、EB、Iba-1表达水平显著高于假手术组,Dex组小鼠大脑海马区HMGB1、RAGE、EB、Iba-1表达水平显著低于脓毒症组(P<0.05)。脓毒症组小鼠外周血及大脑海马区TNF-α、IL-6、IL-1β水平均显著高于假手术组(P<0.05);Dex组小鼠外周血及大脑海马区IL-6、IL-1β水平均显著低于脓毒症组(P<0.05)。结论Dex可改善脓毒症小鼠外周和大脑海马区神经炎症反应,减轻脓毒症导致的血脑屏障通透性升高程度,有利于促进神经认知功能的恢复。

Objective To investigate the effect of Dexmedetomidine(Dex)on the recovery of neurocognitive function by reducing neuroinflammatory reactions in the periphery and hippocampus of septic mice.Methods A total of 51 CD1 mice were randomly divided into sham operation group(n=17),sepsis group(n=17)and Dex group(n=17).Sham operation group only underwent laparotomy and cecal exposure.Septic mouse models were established by cecal ligation and perforation in the remaining other two groups.After the successful modeling,Dex group was injected with Dex intraperitoneally,while sham operation and sepsis groups were injected with normal saline intraperitoneally at the same time point.The learning and memory ability(time to enter the target box)and stiffness times of fear experiment under different conditions were observed after treatment for 1,2,3 and 4 d,and levels of high mobility group protein 1(HMGB1),receptor for advanced glycation end product(RAGE),Iba-1,Evans blue(EB),tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)and peripheral blood levels of TNF-α,IL-6 and IL-1βwere compared in groups.Results After treatment for 1,2,3 and 4 d,times to enter the target box in sepsis group were significantly longer than those in sham operation group,and times to enter the target box in Dex group were significantly shorter than those in sepsis group(P<0.05).In the environment and sound-related fear conditioning test,the stiffness time in sepsis group was significantly shorter than that in sham operation group,while the stiffness time in Dex group was significantly longer than that in sepsis group(P<0.05).Expressions of HMGB1,RAGE,EB and Iba-1 in hippocampus in sepsis group were significantly higher than those in sham operation group,and expressions of HMGB1,RAGE,EB and Iba-1 in hippocampus in Dex group were significantly lower than those in sepsis group(P<0.05).Levels of TNF-α,IL-6 and IL-1βin peripheral blood and cerebrum hippocampus in Dex group were significantly higher than those in sham operation group(P<0.05),and levels of IL-6 and IL-1βin peripheral blood and in hippocampus in Dex group were significantly lower than those in sepsis group(P<0.05).Conclusion Dex may improve the peripheral and hippocampal neuroinflammatory reactions,reduce the increase of blood-brain barrier permeability caused by sepsis and promote the recovery of neurocognitive function in septic mice.