Suvorexant改善慢性睡眠剥夺小鼠学习记忆损害的机制探讨  

Study on the mechanism of Suvorexant treatment ameliorates learning and memory impairment in chronic sleep deprivation mice model

作　　者：邵娜 殷昊 李亚冉 张保坤 黄伟伟[2] 鲁珊珊[2] 唐吉友 SHAO Na;YIN Hao;LI Yaran;ZHANG Baokun;HUANG Weiwei;LU Shanshan;TANG Jiyou(Department of Neurology,Shandong Provincial Qianfoshan Hospital,Cheeloo College of Medicine,Shandong University,Jinan 250014,Shandong,China;Department of Neurology,The First Affiliated Hospital of Shandong First Medical University&Shandong Provincial Qianfoshan Hospital,Shandong Institute of Neuroimmunology,Shandong Key Laboratory of Rheumatic Disease and Translation Medicine.Jinan 250014,Shandong,China)

机构地区：[1]山东大学齐鲁医学院,山东省千佛山医院神经内科,山东济南250014 [2]山东第一医科大学第一附属医院(山东省千佛山医院)神经病学,山东省神经免疫研究所,山东省风湿免疫病转化医学重点实验室,山东济南250014

出　　处：《山东大学学报（医学版）》2022年第4期17-23,共7页Journal of Shandong University:Health Sciences

基　　金：国家自然科学基金(81471345);山东省自然科学基金(ZR2020MH160)

摘　　要：目的观察Orexin双受体拮抗剂(Suvorexant)对慢性睡眠剥夺模型小鼠学习记忆的影响,探讨星形胶质细胞在Orexin系统影响睡眠剥夺小鼠学习记忆过程中的作用。方法8~10周的野生型小鼠随机分为对照组、溶剂对照组、睡眠剥夺组和Suvorexant干预组,通过睡眠剥夺仪器模拟人工轻抚的方式对小鼠进行睡眠干扰4周,每天干预20 h,Suvorexant干预组在睡眠剥夺期间同时给予Suvorexant腹腔注射(30 mg/kg,4周);通过Morris水迷宫评价小鼠空间学习记忆,并通过免疫组化和蛋白质印迹观察Orexin-A在下丘脑外侧区的表达改变以及星形胶质细胞标记物胶质纤维酸性蛋白(GFAP)在小鼠海马区的表达情况。结果睡眠剥夺4周后Orexin-A在下丘脑外侧区表达明显增加;干预期间各组小鼠体质量改变无差异;Suvorexant治疗对慢性睡眠剥夺小鼠的学习记忆有明显的改善作用,与睡眠剥夺组相比,小鼠逃避潜伏期降低,平台穿越次数增多(P<0.05);GFAP蛋白在睡眠剥夺小鼠海马表达量增多。形态学表现为细胞呈反应性,即胞体增大,突触变长,阳性表达明显增多;而与睡眠剥夺组相比,Suvorexant干预组小鼠GFAP表达减少,差异有统计学意义(P<0.05)。结论Suvorexant干预可改善慢性睡眠剥夺小鼠的空间学习记忆,并减少海马区反应性星形胶质细胞的表达,提示反应性星形胶质细胞可能参与这一过程。Objective To observe the effects of Orexin dual receptor antagonist(Suvorexant)on learning and memory in chronic sleep deprivation(SD)mice,and to explore the role of astrocytes in Orexin system affecting learning and memory in SD mice model.Methods Wild-type mice aged 8-10 weeks were randomly divided into 4 groups:control group,saline control group,chronic SD group and Suvorexant intervention group.The mice were subjected to sleep disturbance for 4 weeks by simulating artificial stroking with a sleep deprivation chamber with 20 hours per day.And during SD,the Suvorexant intervention group was given an intraperitoneal injection of Suvorexant at the same time(30 mg/kg,4 weeks);the spatial learning and memory of mice were evaluated with Morris water maze,and the expression of Orexin-A in the lateral hypothalamus and the expression of astrocyte marker glialfibrillary acidic protein(GFAP)in the hippocampus were observed with immunohistochemistry and Western blotting.Results The expression of Orexin-A was significantly increased in the lateral hypothalamus after 4 weeks of SD,and there was no difference in body weight among the groups during the intervention.Suvorexant treatment significantly improved learning and memory after chronic SD.Compared with the SD group,the Suvorexant intervention group had decreased escape latency and an increased number of platform crossings(P<0.05).The expression of GFAP protein increased in the hippocampus of SD mice,and the morphological manifestations showed that the cells were reactive:the cell body was enlarged,the synapse became longer,and the expression in the positive area was significantly increased.Compared with the SD group,the Suvorexant intervention group had decreased expression of GFAP(P<0.05).Conclusion Suvorexant treatment improves spatial learning and memory in chronic SD mice and reduces the expression of reactive astrocytes in the hippocampus,and the activation of astrocytes may be involved in this process.

关 键 词：Orexin双受体拮抗剂 慢性睡眠剥夺 学习记忆 星形胶质细胞 海马 

分 类 号：R740[医药卫生—神经病学与精神病学]