摘要
目的评价抗抑郁新药盐酸羟哌吡酮(代号:YL-0919)对脂多糖(LPS)诱导的小鼠抑郁样和焦虑样行为的作用及对LPS诱导的BV2细胞炎症因子转录水平的影响。方法①将雄性C57BL/6J小鼠随机分为正常对照组、模型组、模型+YL-0919组和模型+YL-0919+BD1047(Sigma-1受体拮抗剂)组,在实验第1天和第6天分别ip给予小鼠LPS 0.5 mg·kg^(-1),并于第2~6天每天2次ig给予YL-09192.5 mg·kg^(-1),或同时每天1次伴随ip给予BD10474 mg·kg^(-1)。以开场实验评价小鼠自发活动和焦虑样行为,以强迫游泳实验评价小鼠抑郁样行为。Western印迹法检测各组小鼠前额叶皮质NOD样受体热蛋白结构域相关蛋白3(NLRP3)和白细胞介素1β(IL-1β)蛋白表达水平。②BV2细胞分为细胞对照组、LPS组(LPS 1 mg·L^(-1)孵育6 h)、LPS+YL-0919组(YL-09192μmol·L^(-1)预处理1 h后加入LPS 1 mg·L^(-1)孵育6 h)和LPS+YL-0919+NE-100组(同时给予YL-09192μmol·L^(-1)和Sigma-1受体拮抗剂NE-10010μmol·L^(-1)预处理1 h后加入LPS 1 mg·L^(-1)孵育6 h),用实时荧光定量PCR(RT-qPCR)检测BV2细胞内IL-6和IL-1βmRNA表达水平。结果①与正常对照组相比,LPS模型组小鼠自发活动无显著变化,但开场实验中央区的停留时间和进入中央区次数显著减少(P<0.05,P<0.01),强迫游泳不动时间显著延长(P<0.01),前额叶皮质IL-1β和NLRP3蛋白表达明显上调(P<0.05);与LPS模型组相比,模型+YL-0919组上述变化显著逆转(P<0.05,P<0.01);而该逆转作用可被BD1047所阻断(P<0.05,P<0.01)。②与细胞对照组比较,LPS模型组BV2细胞IL-1β和IL-6 mRNA水平上调(P<0.01);与LPS模型组相比,模型+YL-0919组细胞上述变化显著逆转(P<0.01),该作用可被NE-100所阻断(P<0.05)。结论YL-0919可对抗LPS模型小鼠的焦虑样/抑郁样行为效应,并抑制LPS诱导的BV2细胞炎症因子转录水平的增加,其机制可能由Sigma-1受体介导。
OBJECTIVE To evaluate the effect of hypidone hydrochloride(code:YL-0919)on depression-and anxiety-like behaviors of lipopolysaccharide(LPS)-treated mice,and on the transcription levels of inflammatory factors in LPS-treated BV2 cells.METHODS①Male C57BL/6J mice were divided into the normal control group,model group,model+YL-0919 group and model+YL-0919+BD1047(a Sigma-1 receptor antagonist)group.On the first and sixth days of the experiment,mice were given LPS(0.5 mg·kg^(-1),ip).From the second to the sixth days of the experiment,YL-0919(2.5 mg·kg^(-1),twice a day,ig)was administered alone or co-administered with BD1047(4 mg·kg^(-1),once per day,ip).The spontaneous activity and anxiety-like behavior were evaluated via the open field test,and the depression-like behavior was tested via the forced swimming test in mice.Western blotting was used to detect the expressions of NOD-like receptor thermal protein domain associated protein 3(NLRP3)and inflammatory factor inter⁃leukin-1β(IL-1β)in the prefrontal cortex of mice.②BV2 cells were divided into the cell control group,LPS group(LPS 1 mg·L^(-1)incubation for 6 h),LPS+YL-0919 group(one hour of pre-administration of YL-09192μmol·L-1,followed by six hours of LPS 1 mg·L^(-1)incubation)and LPS+YL-0919+NE-100(a Sigma-1 receptor antagonist)group(one hour of pre-administration of YL-09192μmol·L^(-1)and NE-10010μmol·L-1,followed by six hours of LPS 1 mg·L^(-1)incubation).Real-time quantitative PCR(RT-qPCR)was used to detect the effect of YL-0919 pretreatment on mRNA levels of inflammatory factors IL-6 and IL-1βof LPStreated(LPS 1 mg·L-1,6 h)BV2 cells.RESULTS①Compared with the normal control group,there was no significant change in spontaneous activity in the LPS model group,but the time spent in the center zone and entries into the center were significantly reduced(P<0.05,P<0.01)in the open field test,while immobility time was significantly prolonged(P<0.01)in the forced swimming test.The expressions of NLRP3 and IL-1βin the prefrontal cortex were sign
作者
常海霞
崔林雨
李云峰
代威
张继国
CHANG Haixia;CUI Linyu;LI Yunfeng;DAI Wei;ZHANG Jiguo(College of Pharmacy,Shandong First Medical University&Shandong Academy of Medical Sciences,Taian 271016,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)
出处
《中国药理学与毒理学杂志》
CAS
北大核心
2023年第10期725-732,共8页
Chinese Journal of Pharmacology and Toxicology
基金
国家自然科学基金(82204358)。
关键词
盐酸羟哌吡酮
抑郁
焦虑
炎症
小鼠
BV2细胞
脂多糖
hypidone hydrochloride
depression
anxiety
inflammation
mice
BV2 cells
lipopolysaccharide
