N-甲基-D-天冬氨酸受体阻断剂缓解HIV-1/gp120诱导大鼠学习记忆障碍的作用及机制  

Effect of NMDA receptor blocker in relieving HIV-1/gp120 induced learning and memory disorder in rats and its mechanism

作　　者：梁美 余佳佳 项锡勇 夏思雨 李珊[1,2] 曾怡蓉 王俪璇 周怡俊 周燕 LIANG Mei;YU Jia-jia;XIANG Xi-yong;XIA Si-yu;LI Shan;ZENG Yi-rong;WANG Li-xuan;ZHOU Yi-jun;ZHOU Yan(College of Pharmacy,Guangxi Medical University,Nanning 530021,China;Nursing College,Guangxi Medical University,Nanning 530021,China;Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation,Guangxi Medical University,Nanning 530021,China)

机构地区：[1]广西医科大学药学院,广西南宁530021 [2]广西医科大学护理学院,广西南宁530021 [3]广西医科大学生物活性分子研究与评价重点实验室,广西南宁530021

出　　处：《中国药理学通报》2023年第6期1149-1156,共8页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81660213,81360192);广西自然科学基金资助项目(No 2017GXNSFAA198187,2018GXNSFAA281325)。

摘　　要：目的研究阻断N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor,NMDAR)对gp120诱导大鼠学习记忆障碍的缓解作用及机制。方法(1)32只SD大鼠随机分为空白对照组、假手术组、gp120组、gp120+Memantine组。除空白对照组外,其余组均双侧海马注射,建立大鼠学习记忆障碍模型。Memantine于造模前3天腹腔注射给药。注射后第3~8天进行水迷宫实验,第10天分离各组大鼠海马,qRT-PCR检测TNF-α、IL-10、CXCL-12表达。(2)以gp120和NMDA诱导建立细胞损伤模型;将细胞分为空白对照组、gp120组、gp120+Memantine组、NMDA组、NMDA+Memantine组。Memantine需预先处理40 min。MTT、LDH法检测细胞存活率和LDH含量,ELISA法检测细胞IL-1β、TNF-α含量,AO/EB染色检测细胞凋亡,qRT-PCR检测IRE1α、JNK、GRP78和CHOP表达。结果(1)与gp120组相比,gp120+Memantine组逃避潜伏期及游泳距离明显减少,目标象限时间百分比和平台穿越次数增加,TNF-α、CXCL-12的mRNA表达量减少。(2)与gp120组和NMDA组相比,gp120+Memantine组和NMDA+Memantine组细胞活力上升,细胞状态良好,IL-1β、TNF-α、IRE1α、JNK、GRP78和CHOP的表达量下降。结论NMDAR参与了gp120诱导的HAND,阻断NMDAR可以显著改善gp120诱导的大鼠学习记忆障碍和神经细胞损伤,其机制与抑制神经炎症、凋亡反应和内质网应激相关IRE1α-JNK-CHOP通路有关。Aim To investigate the alleviating effect of NMDA receptor blocking on learning and memory impairment induced by gp120 in rats and its mechanism.Methods(1)Thirty-two SD rats were randomly divided into control group,sham operation group,gp120 group,and gp120+Memantine group.Except for the control group,the other groups underwent a bilateral hippocampal injection to establish the model of learning and memory impairment in rats.Memantine(10 mg·kg-1·d-1)was administered intraperitoneally three days before modeling.The Morris test was performed three to eight days after injection.On 10th day,the hippocampus tissue of rats in each group was separated,and the relative expression level of TNF-α,IL-10 and CXCL-12 were detected by qRT-PCR.(2)The cell damage model was established by gp120 and NMDA induction.PC12 cells were randomly divided into blank control group,gp120 group,gp120+Memantine group,NMDA group,and NMDA+Memantine group.Memantine(8μmol·L^(-1))was used to pretreat the cells for 40 min.Then MTT and LDH methods were used to detect the cell survival rate and the content of lactate dehydrogenase.The ELISA method was employed to detect the contents of TNF-α,IL-1β.AO/EB staining was applied to detect the apoptosis,and qRT-PCR to detect the expression of IRE1-α,JNK,GRP78,and CHOP.Results(1)Compared to gp120 group,the escape latency and swimming distance in the gp120+Memantine group were significantly reduced,the crossing times and the percentage of the distance in the target were raised,and the mRNA expressions of TNF-αand CXCL-12 were reduced.(2)Compared to gp120 and NMDA groups,the gp120+Memantine group and NMDA+Memantine group showed increased cell viability and good cell status and decreased expression levels of IL-1β,TNF-α,IRE1α,JNK,GRP78,and CHOP.Conclusions NMDAR is involved in GP120-induced HAND,and blocking NMDAR can significantly improve GP120-induced learning and memory impairment and nerve cell damage in rats,the mechanism of which is related to inhibition of neuroinflammation,apoptotic response

关 键 词：NMDA受体 GP120 学习记忆障碍 炎症 凋亡 内质网应激 

分 类 号：R-332[医药卫生] R329.24R338.64R341R364.5R392.11