NR2A特异性拮抗剂NVP-AAM077对大鼠海马空间学习和记忆能力的影响  

Effect of NR2A specific antagonist NVP-AAM077 on spatial learning and memory in rats

作　　者：郑峰[1,2] 张子涵 陈建州 金清华 肖斌[1] ZHENG Feng;ZHANG Zi-han;CHEN Jian-zhou;JIN Qing-hua;XIAO Bin(Dept of Physiology and Pathophysiology,College of Medicine,Yanbian University,Yanji,Jilin 133002,China;Dept of Oncology,People's Hospital of Linyi,Linyi,Shandong 276000,China)

机构地区：[1]延边大学医学院生理与病理生理学教研室,吉林延吉133002 [2]临沂市人民医院肿瘤科,山东临沂276000

出　　处：《中国药理学通报》2024年第8期1517-1522,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No.32160195);吉林省自然科学基金资助项目(No.YDZJ202201ZYTS255)。

摘　　要：目的基于经典水迷宫空间记忆行为范式,观察大鼠学习记忆前后N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor,NMDAR)2A亚单位(NR2A)变化,通过海马齿状回微量注射NVP-AAM077(NR2A拮抗剂)探讨其神经药理学作用及可能机制。方法3月龄♂SD大鼠随机分为行为学训练(Training)和未训练(Non-training)两大组,再分别分为对照和齿状回注射NVP-AAM077(NVP)组。Western blot检测齿状回的NR2A、p-eIF2α、ATF4和脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)表达;向NVP组大鼠齿状回注射整合应激反应抑制剂ISRIB,观察齿状回的p-eIF2α水平、ATF4表达及空间记忆能力。结果与Non-training比较,行为学训练促进大鼠齿状回的NR2A和BDNF表达;Training-NVP大鼠齿状回的NR2A和BDNF表达明显减少,p-eIF2α和ATF4表达增加;ISRIB明显抑制ATF4表达,并翻转注射NVP引起的大鼠空间记忆损伤。结论齿状回注射NVP抑制NR2A通路激活并损害大鼠空间记忆,这种作用主要与海马整合应激反应有关。Aim To observe the changes in hippocampal 2A subunit of N-methyl-D-aspartate receptor(NR2A)before and after the learning and memory training,and then investigate the neuropharmacological effects of NR2A by microinjection of NVP-AAM077(NR2A specific antagonist)into the hippocampal denteta gyrus,based on the spatial learning and memory behavior paradigm induced by Mirror water maze training.Methods Three-month old SD rats were randomly divided into the training and non-training group,and the rats in the two groups were randomly divided into control group and NVP-AAM077 group(NVP).The expressions of NR2A,brain-derived neurotrophic factor(BDNF),transcriptional activator 4(ATF4)and eukaryotic transcription initiation factor 2α(eIF2α)phosphorylation levels in denteta gyrus were detected by Western blot.Then,integrated stress response inhibitor ISRIB was microinjected into the dentate gyrus after the NVP,the expression of ATF4 and p-eIF2αlevels,and the spatial memory abilities were detected.Results Compared with non-training,behavioral training promoted the expression of NR2A and BDNF of rats in denteta gyrus,and this effect could be inhibited by NVP,which significantly increased the expression of p-eIF2αand ATF4.Injection of ISRIB into denteta gyrus significantly inhibited the expression of ATF4,and reversed the spatial memory impairment caused by NVP.Conclusion NVP-induced hippocampal dentate gyrus NR2A-mediated spatial learning and memory impairment in rats may be related to hippocampal integrated stress response.

关 键 词：N-甲基-D-天冬氨酸受体2A亚基 NVP-AAM077 海马 齿状回 空间学习和记忆 整合应激反应 

分 类 号：R-332[医药卫生] R322.81R338.64R392.11R916.4