新型褪黑素1型和2型受体激动及5-羟色胺2C受体拮抗剂GW117抗抑郁、抗焦虑作用及机制  

Antidepressant and anxiolytic effects and mechanisms of GW117,a novel melatonin type 1 and type 2 receptor agonist and 5-hydroxytryptamine 2C receptor antagonist

作　　者：杨雅琪 杨秋实[1] 木热扎提·提力瓦尔地 高娜娜 顾为 李晓蓉[1] 金增亮[1] YANG Ya-qi;YANG Qiu-shi;Murezati TILIWAERDE;GAO Na-na;GU Wei;LI Xiao-rong;JIN Zeng-iang(School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China;Department of Pharmacy,Beijing Chaoyang Hospital,Capital Medical University,Beijing 100020;Beijing Shijitan Hospital,Captial Medical University,Beijing 100038,China;Beijing Guangwei Pharmaceutical Technology Co.,Ltd.,Beijing 100044,China)

机构地区：[1]首都医科大学基础医学院,北京100069 [2]首都医科大学附属北京朝阳医院药事部,北京100020 [3]首都医科大学附属北京世纪坛医院胃肠外科与临床营养科,北京100038 [4]北京广为医药科技有限公司,北京100044

出　　处：《中国药理学与毒理学杂志》2023年第6期401-410,共10页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金(81703484);国家自然科学基金(82073828);国家自然科学基金(82273905);国家自然科学基金(82204531);北京市教委自然科学基金(KM2017-10025003);“十三五”北京市属高校高水平教师队伍建设支持计划(CIT&ICD201704095)。

摘　　要：目的评价具有褪黑素1型和2型(MT1/MT2)受体激动及5-羟色胺2C(5-HT2C)受体拮抗作用的新型化合物GW117的抗焦虑和抗抑郁作用,并探究其可能机制。方法ICR小鼠在测定蔗糖偏嗜率基线后,按照蔗糖偏嗜率均衡分为正常对照组、模型组、模型+阳性药阿戈美拉汀(Ago,20和40 mg·kg^(-1))组、模型+GW117(5,10,20和40 mg·kg^(-1))组。正常对照组常规饲养,其余组进行5周慢性不可预知性温和刺激(CUMS)建立CUMS模型。造模5周后开始给药,各组连续ig给药6周后,采用蔗糖偏嗜、强迫游泳、悬尾、高架十字迷宫和新奇抑制摄食实验评价GW117的抗焦虑和抗抑郁行为效应;采用免疫荧光染色法检测小鼠海马齿状回新生神经元密度;高效液相色谱-电化学检测法检测海马组织中神经递质5-HT、多巴胺(DA)和去甲肾上腺素(NE)的含量。结果与正常对照组比较,模型组小鼠在蔗糖偏嗜实验中蔗糖偏嗜率显著降低(P<0.01),强迫游泳实验和悬尾实验中不动时间显著延长(P<0.05,P<0.01),新奇抑制摄食实验中摄食潜伏期显著延长(P<0.01),高架十字迷宫实验中进入开臂时间(OT)百分比和进入开臂次数(OE)百分比显著减少(P<0.01);海马齿状回新生神经元密度和海马组织DA含量显著减少(P<0.05)。与模型组比较,模型+Ago 40 mg·kg^(-1)组和模型+GW117(20和40 mg·kg^(-1))组小鼠蔗糖偏嗜率显著升高(P<0.05,P<0.01);模型+Ago(20和40 mg·kg^(-1))组和模型+GW117(5,10,20和40 mg·kg^(-1))组小鼠强迫游泳不动时间显著缩短(P<0.01);模型+Ago 40 mg·kg^(-1)组和模型+GW117(10,20和40 mg·kg^(-1))组悬尾不动时间和摄食潜伏期显著缩短(P<0.05,P<0.01);模型+Ago 40 mg·kg^(-1)组和模型+GW117(20和40 mg·kg^(-1))组小鼠OE百分比显著增加(P<0.01),模型+Ago 40 mg·kg^(-1)组和模型+GW117(20和40 mg·kg^(-1))组小鼠OT百分比显著增加(P<0.05,P<0.01);模型+Ago(20和40 mg·kg^(-1))组和模型+GW117(10,20和40 mg·kg^(-1))组海马齿状回�OBJECTIVE To evaluate the anxiolytic and antidepressant effects of GW117,a novel compound with melatonin type 1 and type 2(MT1/MT2)receptor agonists and 5-hydroxytryptamine 2C(5-HT2C)receptor antagonists,and to investigate its mechanism.METHODS ICR mice were divided into the normal control,model,model+agomelatine(Ago,20 and 40 mg·kg^(-1))and model+GW117(5,10,20 and 40 mg·kg^(-1))groups according to the baseline of the sucrose preference rate.The normal control group was routinely housed while the other groups were subjected to 5 weeks of chronic unpredictable mild stress(CUMS)to establish a CUMS model.The drug was administered 5 weeks after modeling,and each group was ig administered for 6 consecutive weeks.The anxiolytic and antidepressant effects were evaluated using the sucrose preference test(SPT),forced swimming test(FST),tail suspension test(TST),elevated plus maze test(EPMT)and novelty-suppressed feeding test(NSFT).The neonatal neurons in the hippocampal dentate gyrus of mice were measured by immunofluorescence staining,and the contents of neurotransmitter 5-hydroxytryptamine(5-HT),dopamine(DA)and norepinephrine(NE)in hippocampal tissue were measured by high performance liquid chromatography-electrochemical assay.RESULTS Compared with the normal control group,the rate of sucrose preference in SPT was significantly decreased(P<0.01),the immobility time in FST and TST was significantly increased(P<0.05,P<0.01),so was the feeding latency in NSFT(P<0.01).The percentage of time in the open arms(OT)and the percentage of entries in the open arms(OE)in EPMT were significantly reduced(P<0.01)in the model group,so was the density of neonatal neurons in the hippocampal dentate gyrus and the DA content of hippocampal tissue(P<0.05).Compared with the model group,the rate of sucrose prefer-ence in SPT in the model+Ago 40 mg·kg^(-1) and model+GW117(20 and 40 mg·kg^(-1))groups was signifi-cantly increased(P<0.05,P<0.01),the immobility time in FST in the model+Ago(20 and 40 mg·kg^(-1))and model+GW117(5,10,20 and 40 mg

关 键 词：抑郁症 焦虑症 GW117 褪黑素受体 单胺系统 神经再生 

分 类 号：R964[医药卫生—药理学] R749.4[医药卫生—药学] R749.7