Suvorexant通过调控PER1蛋白表达改善APP/PS1小鼠昼夜节律紊乱行为  

Suvorexant improves abnormal circadian locomotor rhythms in APP/PS1 mice by modulating PER1 expression

作　　者：周芳 魏佳慧 白羽 朱洪伟 赵芳[1] 张秀敏 祁金顺[1] 武美娜[1] Zhou Fang;Wei Jiahui;Bai Yu;Zhu Hongwei;Zhao Fang;Zhang Xiumin;Qi Jinshun;Wu Meina(Shanxi Medical University Department of Physiology,Key Laboratory of Cellular Physiology,Ministry of Education,Taiyuan 030001,China;Shanxi Medical University The Second Affiliated Hospital of Shanxi Medical University,Taiyuan 030001,China)

机构地区：[1]山西医科大学生理学系,细胞生理学教育部重点实验室,太原030001 [2]山西医科大学第二临床医学院,太原030001

出　　处：《神经解剖学杂志》2019年第4期400-406,共7页Chinese Journal of Neuroanatomy

基　　金：山西省青年三晋学者人才计划;山西省优秀青年基金项目(201801D211005);国家级大学生创新创业训练计划项目(201810114002);山西省“1331工程”重点学科建设计划经费资助

摘　　要：目的:探讨orexin双受体拮抗剂suvorexant对9月龄APPswe/PS1dE9(APP/PS1)双转基因小鼠行为昼夜节律紊乱的影响及机制。方法:8月龄APP/PS1小鼠和具有同样遗传背景的野生型(WT)小鼠随机分为4组,在ZT0口服灌胃suvorexant或等体积溶剂28 d,采用跑轮行为学观察小鼠昼夜节律变化,免疫组织化学和Western Blot分别检测SCN脑区Aβ斑块和PER1蛋白的表达。结果:(1)在光暗交替环境中,给予suvorexant后APP/PS1小鼠相对振幅(P<0.01)和鲁棒值(P<0.01)明显升高,昼夜变异性明显降低(P<0.01)。(2)在持续黑暗环境中给予suvorexant后,APP/PS1小鼠的自由运转周期明显缩短(P<0.05),活动持续时间缩短(P<0.01),相对振幅增大(P<0.01),昼夜变异性减小(P<0.01)。(3)免疫组化结果显示各组动物的SCN脑区未检测到Aβ阳性斑块。(4)APP/PS1小鼠给予Suvorexant后部分恢复了PER1蛋白表达的昼夜节律性。结论:suvorexant通过恢复SCN脑区PER1的昼夜节律性表达改善APPswe/PS1dE9小鼠的昼夜节律紊乱,增强其昼夜节律稳定性。Objective:To observe the effects of suvorexant,an orexin double receptor antagonist,on abnormal circadian locomotor rhythms appeared in 9-month-old APPswe/PS1 dE9(APP/PS1)double transgenic mice and investigate the possible mechanisms.Methods:8-month-old APP/PS1 mice and control mice of same genetic background were randomly divided into 4 groups,and were continuously orally administered with suvorexant(30 mg/kg)or vehicle at ZT0 for 28 days.Wheel-running activities were monitored to observe the circadian rhythm.Then,the Aβdeposition was observed by immunohistochemistry and the expression of PER1 protein was investigated by Western Blot.Results:(1)At light-dark cycle condition,suvorexant treatment increased the the relative amplitude(P<0.01)and robustness(P<0.01),and significantly decreased the intradaily variability(IV)(P<0.01).(2)In constant dark environment,administration of suvorexant significantly shortened the free running period of APP/PS1 mice(P<0.05),along with the increase of relative amplitude(P<0.01).The shortening of activity duration(P<0.01)was accompanied by the decrease of IV(P<0.01).(3)Immunohistochemistry results showed that there was no obvious Aβpositive plaques observed in the SCN in each group.(4)Suvorexant treatment partially restored the circadian rhythm of PER1 protein expression in APP/PS1 mice.Conclusion:Suvorexant effectively alleviates the locomotor circadian disturbance by recovering the circadian rhythm expression of PER1 in SCN of APP/PS1 mice.

关 键 词：suvorexant 阿尔茨海默病 昼夜节律 PER1 APPswe/PS1dE9双转基因小鼠 

分 类 号：R749.16[医药卫生—神经病学与精神病学]