桂皮醛通过阻止海马神经炎症反应改善阿尔茨海默病老年小鼠记忆障碍的作用研究  

A Study on the Effects of Trans-cinnamaldehyde on Improving Memory Impairment by Suppression of Neuroinflammatory Responses in Hippocampus of Aged Mice with Alzheimer’s Disease

作　　者：吴永康 高洁 卢志园 顾祎宁 赵晨怡 巴宗韬 王星禹[1] 杨建梅[3] 徐颖[1] Wu Yongkang;Gao Jie;Lu Zhiyuan;Gu Yining;Zhao Chenyi;Ba Zongtao;Wang Xingyu;Yang Jianmei;Xu Ying(Department of Physiology,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Department of Traditional Reh abilitation,School of Reh abilitation Science,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Department of Traditional Chinese Medicine,Xuhui District Central Hospital,Shanghai 200031,China)

机构地区：[1]上海中医药大学生理教研室,上海201203 [2]上海中医药大学康复医学院,上海201203 [3]上海市徐汇区中心医院中医科,上海200031

出　　处：《世界科学技术-中医药现代化》2021年第5期1627-1635,共9页Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology

基　　金：国家自然科学基金委员会面上项目(81274119):NF-κB/MAPKs-NMDAR-αCa MKII通路介导桂皮醛对PS1/PS2双敲除AD小鼠神经炎症和学习记忆的作用,负责人:徐颖;上海市卫生健康委员会项目(2020JCGZS-018):《杨建梅上海市基层名老中医专家传承工作室》建设项目,负责人:杨建梅;上海市卫生健康委员会项目:上海市进一步加快中医药事业发展三年行动计划(2018-2020)中医重点专科培育项目(中医脑病专科),负责人:杨建梅。

摘　　要：目的探讨桂皮醛(trans-cinnamaldehyde,TCA)对老年具有阿尔茨海默病(Alzheimer’s disease,AD)样表型的早老素1/2条件性双基因敲除(Presenilin1/2 conditional double knockout,PS cDKO)小鼠海马神经炎症反应和突触破坏导致的记忆障碍的改善作用及其机制研究。方法选用9月龄PS cDKO小鼠和其同窝野生型对照小鼠随机分为四组:野生型组(wildtype,WT)、野生型+TCA(WT+TCA)、PS cDKO组(cDKO)和PS cDKO+TCA组(cDKO+TCA),每组10只。WT+TCA和cDKO+TCA组的小鼠给予含有TCA(240ppm)的饲料治疗,WT和cDKO组的小鼠给予普通饲料,共治疗90 d,治疗60 d后进行行为学测试,测试期间继续进行治疗,测试结束后取小鼠海马进行分子生物学实验。其中,Morris水迷宫实验观察TCA治疗后对PS cDKO小鼠空间参考记忆的影响,恐惧实验检测TCA对PS cDKO小鼠联合记忆能力的影响;Western Blot检测TCA对PS cDKO小鼠海马突触蛋白表达的影响;RT-PCR检测TCA对PS cDKO小鼠海马促炎症因子mRNA水平的影响。结果TCA明显改善PS cDKO小鼠的空间参考记忆障碍(P<0.05)和联合记忆损伤(P<0.05)。另外,TCA上调PS cDKO小鼠海马中N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR)的亚基NR1和NR2A、突触小泡蛋白(Synaptophysin,SYP)的蛋白表达,下调Tau蛋白的过度磷酸化;同时,TCA降低海马促炎症因子白介素-1β(interleukin-1β,IL-1β)、诱导性一氧化碳酶(inducible nitricoxide synthase,iNOS)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、环氧合酶-2(cyclooxygenase-2,COX-2)的m RNA水平(P<0.05)。结论TCA改善老年PS cDKO小鼠记忆障碍可能是通过抑制海马的神经炎症反应并提高突触蛋白的表达来发挥神经保护作用。Objective To explore the improving effects and mechanism of trans-cinnamaldehyde(TCA)on memory impairment caused by hippocampal neuroinflammatory response and synapse destruction in Presenilin1/2 conditional double knockout mice with Alzheimer’s disease(AD)-like phenotype at 12 months of age.Methods 9-month-old PS cDKO mice and their littermate wild-type control mice were randomly divided into four groups:wild-type group(WT),wild-type+TCA(WT+TCA),PS cDKO group(cDKO)and PS cDKO+TCA group(cDKO+TCA),with 10 mice in each grou The mice in the WT+TCA and cDKO+TCA groups were treated with feed containing TCA(240 ppm),and the mice in the WT and cDKO groups were treated with ordinary feed for a total of 90 days,followed by a behavioral test on day 60.After behavioral test,we conducted molecular biology analyses.Among them,the we observed the effect of TCA treatment on the spatial reference memory in PS cDKO mice by using Morris water maze test,and the combined memory ability of PS cDKO mice by using fear conditioning test.Western blot analysis detected the effects of TCA on the expression levels of the hippocampal synaptic protein in PS cDKO mice.RT-PCR analysis detected the influence of TCA on the mRNA level of pro-inflammatory factors in the hippocampus of PS cDKO mice.Results TCA significantly improved the spatial reference memory and combined memory impairment(P<0.05)in PS cDKO mice.In addition,TCA up-regulated the N-methyl-D-aspartate receptor(NMDAR)subunits NR1 and NR2 A,and synaptophysin(SYP)in the hippocampus of PS cDKO mice.TCA down-regulates the hyperphosphorylation of tau protein.At the same time,TCA reduces the mRNA levels of pro-inflammatory mediators(P<0.05),such as interleukin-1β(IL-1β),inducible nitric oxide synthase(iNOS),tumors necrosis factor-α(TNF-α),and cyclooxygenase-2(COX-2)in the hippocampus of PS cDKO mice.Conclusion TCA may play a neuroprotective role in improving memory impairment by rescuing synaptic protein deficits through inhibition of neuroinflammatory response in hippocampus of PS cD

关 键 词：反式桂皮醛 阿尔茨海默病 海马 神经炎症 记忆障碍 

分 类 号：R285.5[医药卫生—中药学]