肝X受体激动剂GW3965对应激小鼠海马小胶质细胞活化的影响

The effects of liver X receptor agonist GW3965 on microglia activation in the hippocampus of stressed mice

目的:研究肝X受体(LXRs)激动剂GW3965对慢性不可预知性应激(CUS)抑郁模型小鼠海马CA1、CA2/3和DG区内小胶质细胞密度和神经炎症的作用。方法:选取4~6周龄的雄性C57BL/6J小鼠,适应性喂养1周后,随机分为对照组(control)、对照+GW组(GW)、抑郁模型组(CUS)以及抑郁模型+GW组(CUS+GW)。对CUS组和CUS+GW组小鼠进行10周的CUS干预;从第7周起,对GW组和CUS+GW组小鼠进行4周的GW3965给药。第10周末进行行为学测试后运用免疫荧光方法评估小鼠海马各亚区内小胶质细胞的密度,并采用Western Blot检测海马炎症因子的水平。结果:10周的CUS干预显著减少C57小鼠的体重以及糖水偏好实验结果,并显著增加强迫游泳实验中小鼠的不动时间;4周的GW3965治疗可以逆转以上结果。CUS干预显著增加小鼠海马CA1区、CA2/3区和DG区内Iba1^(+)小胶质细胞密度,以及海马炎症因子IL-1β、TNF-α和转录因子NF-κB的蛋白表达水平,显著降低抗炎介质CD206的蛋白表达水平;而GW3965治疗可逆转上述变化。结论:LXRs可能通过抑制海马各亚区小胶质细胞活化和神经炎症发生从而发挥抗抑郁作用。

Objective:To study the effects of liver X receptors(LXR)agonists(GW3965)on the density of microglia and neuroinflammation in the CA1,CA2/3,and DG regions of hippocampus in a depression mice model of chronic unpredictable stress(CUS).Methods:Male C57 BL/6 J mice aged from 4 to 6 weeks were selected and fed for one week,and then randomly divided into control group,GW group,CUS group,and CUS+GW group.The mice in the CUS group and CUS+GW group were given CUS intervention for 10 weeks.From the 7 th week,mice in the GW group and CUS+GW group were administered GW3965 for 4 weeks.At the end of the 10 th week,behavioral tests were performed,and then immunofluorescence was used to evaluate the density of microglia in hippocampal subregions,and Western Blot technology was used to detect the level of hippocampal inflammatory factors.Results:10 weeks of CUS intervention significantly reduced the body weight of C57 mice and the results of sucrose preference experiment,and significantly increased the immobility time of the mice in the forced swimming experiment.CUS intervention significantly increased the density of Iba1^(+)microglia in the CA1,CA2/3 and DG of the hippocampus,as well as the protein expression levels of IL-1β,TNF-αand NF-κB,and significantly reduced the expression of CD206.While GW3965 treatment could reverse the above changes.Conclusion:LXRs may play an antidepressant effect by inhibiting microglia activation and neuroinflammation in hippocampal subregions.