新型5-羟色胺和去甲肾上腺素重摄取抑制剂ZBH2012001通过增强单胺系统功能和抑制神经免疫炎症发挥抗抑郁作用  

ZBH2012001,a novel serotonin and norepinephrine reuptake inhibitor,exerts antidepressant effect via dual mechanism of monoamine enhancement and inflammation suppression

作　　者：张静雯 范琼尹 张苏素 张杨 罗亚 沈鑫明 罗陆遥 董蓓蕾 李劲草 李硕 董华进 李行舟 何宇鹏 薛瑞 张有志 ZHANG Jingwen;FAN Qiongyin;ZHANG Susu;ZHANG Yang;LUO Ya;SHEN Xinming;LUO Luyao;DONG Beilei;LI Jincao;LI Shuo;DONG Huajin;LI Xingzhou;HE Yupeng;XUE Rui;ZHANG Youzhi(School of Pharmacy,Qingdao University,Qingdao 266073,China;Beijing Key Laboratory of Neuropsychopharmacology,State Key Laboratory of National Security Specially Needed Medicines,Academy of Millitary Medical Sciences,Beijing 100850,China;Ningbo Institute of Dalian University of Technology,Ningbo 315016,China)

机构地区：[1]青岛大学药学院,山东青岛266073 [2]军事科学院军事医学研究院国家安全特需药品全国重点实验室,神经精神药理学北京市重点实验室,北京100850 [3]大连理工大学宁波研究院,浙江宁波315016

出　　处：《中国药理学与毒理学杂志》2024年第5期321-334,共14页Chinese Journal of Pharmacology and Toxicology

摘　　要：目的 基于调节单胺系统功能和神经免疫炎症研究新型5-羟色胺和去甲肾上腺素重摄取抑制剂(SNRI)ZBH2012001的抗抑郁作用机制。方法 (1)雄性ICR小鼠分为溶剂组(蒸馏水)、度洛西汀组(10或20 mg·kg^(-1))、ZBH2012001组(5,10和20 mg·kg^(-1)),ig给药1 h后采用小鼠悬尾实验(TST)和强迫游泳实验(FST)2个行为绝望模型评价ZBH2012001的抗抑郁作用。(2)采用放射性配体结合实验评价ZBH2012001与人源5-HT转运蛋白(hSERT)和NE转运蛋白(hNET)的靶标亲和力。(3)雄性ICR小鼠分为溶剂组(蒸馏水),度洛西汀组(10或20 mg·kg^(-1))和ZBH2012001组(5,10和20 mg·kg^(-1));ig给药1 h后采用小鼠5-羟色氨酸(5-HTP)诱导甩头实验、育亨宾毒性增强实验初步评价ZBH2012001对5-羟色胺(5-HT)和去甲肾上腺素(NE)系统功能的影响。(4)雄性ICR小鼠分为溶剂组(蒸馏水+0.1%冰醋酸),利血平模型组(蒸馏水+利血平5 mg·kg^(-1)),度洛西汀(度洛西汀20 mg·kg^(-1)+利血平5 mg·kg^(-1))组及ZBH2012001(ZBH2012001 5,10和20 mg·kg^(-1)+利血平5 mg·kg^(-1))组,ig给予ZBH2012001 1 h后ip注射利血平:通过观察眼睑下垂、体温下降和运动不能行为评价ZBH2012001对利血平诱导的单胺系统功能下调的影响;采用TST评价ZBH2012001对利血平诱导的抑郁样行为的影响;采用高效液相色谱-电化学检测法(HPLC-ECD)检测利血平单胺耗竭模型小鼠海马组织中单胺递质及其代谢产物的含量;采用ELISA检测利血平诱导单胺耗竭模型小鼠海马组织中肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)的含量;采用Western印迹法检测利血平诱导单胺耗竭模型小鼠海马组织中离子化钙结合适配分子1(Iba-1)和核因子κB(NF-κB)的表达。结果 (1)与溶剂组相比,ZBH2012001(5,10和20 mg·kg^(-1))显著减少小鼠在TST中的不动时间(P<0.01),ZBH2012001(20 mg·kg^(-1))显著减少FST中的不动时间(P<0.05)。(2) ZBH2012001可竞争抑制[^(3)H]-丙咪嗪与hSERT和[^(3)H]-尼索西�OBJECTIVE To evaluate the mechanisms underlying the antidepressant effect of ZBH2012001,a novel serotonin and norepinephrine reuptake inhibitor(SNRI),in general and its ability to enhance monoaminergic transmission and suppress neuroinflammation in particular.METHODS①Male ICR mice were divided into vehicle(distilled water),duloxetine(DLX,10 or 20 mg·kg^(-1))and ZBH2012001(5,10 and 20 mg·kg^(-1))groups.One hour following ig administration,the antidepressant effect of ZBH2012001 was evaluated using the tail suspension test(TST)and forced swimming test(FST).②Radioligand binding assay was conducted to evaluate the affinity of ZBH2012001 for human serotonin transporters(hSERTs)and human norepinephrine transporters(hNETs).③Mice were divided into vehicle(distilled water),DLX(10 or 20 mg·kg^(-1))and ZBH2012001(5,10 and 20 mg·kg^(-1))groups.One hour following drug administration,the 5-hydroxytryptophan(5-HTP)-induced head-twitch test or yohimbine-induced lethality test were performed to evaluate the effect of ZBH2012001 on the function of the 5-hydroxytryptamine(5-HT)and norepinephrine(NE)systems.④Mice were divided into vehicle(distilled water+0.1%acetic acid),reserpine model(distilled water+reserpine 5 mg·kg^(-1)),DLX(DLX 20 mg·kg^(-1)+reserpine 5 mg·kg^(-1))and ZBH2012001(ZBH20120015,10 and 20 mg·kg^(-1)+reserpine 5 mg·kg^(-1))groups.One hour following drug administration,reserpine was injected intraperitoneally to establish a monoamine-depletion model.The ptosis,akinesia,and hypothermia assays were performed to evaluate the effect of ZBH2012001 on the down-regulation of the reserpine-induced monoamine system.The TST in mice was used to evaluate the effect of ZBH2012001 on reserpine-induced depressive-like behavior while high-performance liquid chromatography with electrochemical detection(HPLC-ECD)was used to measure the levels of monoamines and their metabolites in the hippocampal tissue of reserpine-induced monoamine-depletion mice.ELISA was employed to detect the contents of tumor necrosis factor-al

关 键 词：重度抑郁障碍 ZBH2012001 5-羟色胺和去甲肾上腺素重摄取抑制剂 单胺 神经炎症 

分 类 号：R965[医药卫生—药理学]