用皮质酮替代饮水小鼠模型评价盐酸羟哌吡酮的抗抑郁效应及机制  

Antidepressant effect and possible mechanisms of hypidone hydrochloride in corticosterone replacement drinking water model in mice

作　　者：房鑫鑫 麻慧 鲍金豪 王川 李云峰 张黎明 聂晶 FANG Xin-xin;MA Hui;BAO Jin-hao;WANG Chuan;LI Yun-feng;ZHANG Li-ming;NIE Jing(Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,Zunyi Medical University,Zunyi 563003,China;Institute of Military Cognitive and Brain Sciences,Academy of Military Medical Sciences,Beijing 100850,China;Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Beijing 100850,China;Graduate School of Hebei North College,Zhangjiakou 075000,China)

机构地区：[1]遵义医科大学基础药理教育部重点实验室暨特色民族药教育部国际合作联合实验室,贵州遵义563099 [2]军事科学院军事医学研究院军事认知与脑科学研究所,北京100850 [3]军事科学院军事医学研究院毒物药物研究所,北京100850 [4]河北北方学院研究生院,河北张家口075000

出　　处：《中国药理学与毒理学杂志》2022年第5期329-337,共9页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金(81773708);国家自然科学基金(81173036)。

摘　　要：目的制备皮质酮(CORT)替代饮水小鼠抑郁样模型,评价盐酸羟哌吡酮(代号:YL-0919)的抗抑郁效应及可能机制。方法选用成年雄性C57BL/6小鼠,随机分为正常对照组与CORT替代饮水组,其中正常对照组正常饮水,CORT替代饮水组饮用CORT半琥珀酸酯水溶液(25 mg·L^(-1))。饲养21 d后进行蔗糖偏好实验(SPT),随后将CORT替代饮水组小鼠随机分为模型组、模型+YL-0919(1.25,2.5和5 mg·kg^(-1))组和模型+氟西汀(Flx,10 mg·kg^(-1))组,慢性ig给药16 d。先后采用旷场实验(OFT)、强迫游泳实验(FST)、悬尾实验(TST)、新物体识别实验(NORT)、新奇抑制摄食实验(NSFT)和SPT评价YL-0919抗抑郁效应;采用免疫荧光法检测双侧海马齿状回双皮质素(DCX)阳性细胞数;Western印迹法检测双侧海马组织内突触后致密蛋白95(PSD95)表达水平。结果与正常对照组相比,模型组小鼠在FST和TST中的不动时间显著增加(P<0.01),在SPT中蔗糖偏嗜度显著降低(P<0.01),在NSFT中摄食潜伏期显著增加(P<0.01),在OFT中心区累计停留时间明显缩短(P<0.01),在NORT中小鼠物体识别指数显著下降(P<0.01);免疫荧光和Western印迹法检测结果表明,与正常对照组相比,模型组小鼠海马齿状回DCX阳性细胞数显著减少(P<0.05),PSD95表达水平显著下调(P<0.01)。与模型组相比,模型+YL-0919组和模型+Flx组小鼠上述变化均明显逆转(P<0.05)。结论YL-0919慢性给药在CORT替代饮水小鼠抑郁样模型中具有抗抑郁效应,该效应可能与促进海马神经可塑性密切相关。OBJECTIVE To investigate the antidepressant effect and the possible mechanisms of hydroxypiperone hydrochloride(YL-0919)in a corticosterone(CORT)replacement drinking water model in mice.METHODS Adult male C57BL/6 mice were randomly divided into the normal control group and CORT replacement drinking water group.The CORT replacement drinking water group replaced water into CORT hemisuccinate solution(25 mg·L^(-1)).After 21 d,the sucrose preference test was performed,and the mice in the CORT replacement drinking water group were randomly divided into the model group,model+fluoxetine(Flx,10 mg·kg^(-1))group and model+YL-0919(1.25,2.5 and 5 mg·kg^(-1))group,before the mice were ig given Flx 10 mg·kg^(-1),YL-09191.25,2.5 and 5 mg·kg^(-1) or water(normal control and model group)for 16 d once per day.The open field test(OFT),forced swimming test(FST),tail suspension test(TST),novel object recognition test(NORT),novelty-suppressed feeding test(NSFT),and sucrose preference test(SPT)were performed to evaluate the antidepressant effects.After that,the number of doublecortin(DCX)positive cells in the bilateral hippocampal dentate gyrus was counted by immunofluorescence staining,and the expression of PSD95 in the bilateral hippocampus was detected by Western blotting.RESULTS Compared with the normal control group,the model group significantly increased the immobility time on the FST and the TST(P<0.01),reduced the sucrose preference on the SPT(P<0.01),shortened the duration in the central area on the OFT(P<0.01),reduced recognition indexes on the NORT(P<0.01)and decreased the number of DCX positive cells in the hippocampal dentate gyrus(P<0.05)and the expression level of PSD95(P<0.01).Compared with the model group,the model+fluoxetine group and the model+YL-0919 group could reverse the above changes(P<0.05).CONCLUSION Chronic YL-0919 treatment shows significant antidepressant effect in the CORT replacement drinking water model in mice,which might be related to the promoted hippocampal neural plasticity.

关 键 词：抑郁症 盐酸羟哌吡酮 皮质酮 海马 神经可塑性 

分 类 号：R964[医药卫生—药理学] R965.1[医药卫生—药学]