帕瑞昔布钠预给药可减轻脂多糖诱导的小鼠认知功能损伤及神经炎症反应  

Preadministration of parecoxib sodium attenuates cognitive impairment and neuroinflammation induced by lipopolysaccharide in mice

作　　者：刘近发 庹鹏 谢洁红 吴亚芬 王寿平[1] LIU Jin-fa;TUO Peng;XIE Jie-hong;WU Ya-fen;WANG Shou-ping(Department of Anesthesiology,The Third Affiliated Hospital of Guangzhou Medical University,Guangzhou 510150,Chi na)

机构地区：[1]广州医科大学附属第三医院麻醉科,广东广州510150

出　　处：《中国病理生理杂志》2021年第6期970-977,共8页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81271223);广东省自然科学基金资助项目(No.S2012010009065,No.2014A030313112);广州市科技计划项目(No.201707010379)。

摘　　要：目的:探讨帕瑞昔布钠(PA)预给药对脂多糖(LPS)诱导的小鼠疾病行为模型认知功能改变及神经炎症的影响。方法:雌性C57BL/6J小鼠80只,10~12月龄,随机分为4组(n=20):空白对照组(CON组)、PA组、LPS组和PA预处理组(P+L组)。LPS腹腔注射制备疾病行为模型,PA组和P+L组在注射LPS前1 h按10 mg/kg剂量腹腔注射PA。采用Morris水迷宫实验评价认知功能;ELISA检测血液及海马区IL-1β、IL-6、IL-18、TNF-α和PGE2的表达;HE染色观察肺组织和海马组织的病理形态改变;免疫荧光法观察海马区小胶质细胞和星形胶质细胞的数目;Western blot法检测海马区COX-2、iNOS、NLRP3、ASC及caspase-1蛋白的表达。结果:与CON组相比,LPS组小鼠Morris水迷宫的逃避潜伏期显著延长,目标象限停留时间及穿越平台次数显著减少(P<0.01),IL-1β、IL-6、IL-18、TNF-α和PGE2的含量显著增多(P<0.01),海马CA1区神经元细胞深染,坏死损伤明显,小胶质细胞和星形胶质细胞的数目显著增加(P<0.05),COX-2、iNOS、NLRP3、ASC及caspase-1蛋白表达量显著增加(P<0.01)。而与LPS组相比,PA明显降低小鼠的神经炎症水平,提高小鼠的记忆能力。结论:帕瑞昔布钠预给药对LPS诱发的认知功能障碍和神经炎症具有一定的预防和改善作用,其作用机制可能与特异性拮抗COX-2,抑制中枢小胶质细胞和星形胶质细胞的活化,减少NLPR3炎症小体的激活,从而降低炎症因子的水平有关。AIM:To investigate the effect of preadministration of parecoxib sodium(PA)on cognitive func‐tion changes and neuroinflammation in mice with lipopolysaccharide(LPS)-induced sickness behavior.METHODS:Fe‐male C57BL/6J mice of 10 to 12 months old(n=80)were randomly divided into 4 groups(n=20):blank control(CON)group,PA group,LPS group and PA preadministration(P+L)group.The model of sickness behavior was established by intraperitoneal injection of LPS.The mice in PA group and P+L group were intraperitoneally injected with PA(10 mg/kg)1 h before LPS injection.Morris water maze test was used to evaluate the cognitive function of mice.The levels of IL-1β,IL-6,IL-18,TNF-αand PGE2 in serum and hippocampus were measured by ELISA.HE staining was used to observe the pathological changes of lung tissue and hippocampus.Immunofluorescence method was used to observe the number of mi‐croglia and astrocytes in hippocampus.Finally,the protein levels of COX-2,iNOS,NLRP3,ASC and caspase-1 in hippo‐campus were determined by Western blot.RESULTS:Compared with CON group,the escape latency time of the mice in Morris water maze test in LPS group was significantly prolonged,the target quadrant dwelling time and the number of crossing platforms were significantly decreased(P<0.01),the levels of IL-1β,IL-6,IL-18,TNF-αand PGE2 in serum and hippocampus were significantly increased(P<0.01),neurons in hippocampal CA1 region were deeply stained with obvious necrotic damage,the number of microglia and astrocytes in the hippocampus were significantly increased(P<0.05),and the protein levels of COX-2,iNOS,NLRP3,ASC and caspase-1 in hippocampus were significantly increased(P<0.01).Compared with LPS group,preadministration of PA significantly reduced the levels of neuroinflammation and improved the memory ability of the mice.CONCLUSION:Preadministration of PA attenuates cognitive dysfunction and neuroinflammation induced by LPS,and its mechanism may be related to the specific antagonism against COX-2,inhibi‐tion of activation of central m

关 键 词：帕瑞昔布钠 脂多糖 认知功能 神经炎症 NLRP3炎症小体 

分 类 号：R363.2[医药卫生—病理学] R631[医药卫生—基础医学]