DAPT对慢性社会挫败应激诱导小鼠抑郁样行为的作用及机制

Role and mechanism of DAPT in chronic social defeat stress-induced depressive-like behavior in mice

目的探究DAPT对慢性应激诱导的小鼠抑郁样行为的作用及机制。方法C57BL/6J小鼠给予慢性社会挫败应激(chronic social defeat stress,CSDS)处理10 d以建立抑郁模型,药物处理组小鼠每天腹腔注射DAPT 5 mg·kg^(-1)。通过社会接触、糖水偏爱、旷场、强迫游泳和悬尾实验来评价小鼠的抑郁样行为;采用Western blot检测小鼠海马NLRP3、ASC、caspase-1、TNF-α、p62、Atg7、Atg5和Beclin1蛋白的表达,运用ELISA检测小鼠海马IL-1β和IL-18的表达水平。结果CSDS诱导小鼠出现明显的抑郁样行为,同时增加了小鼠海马NLRP3、ASC、caspase-1的表达和炎症因子TNF-α、IL-1β和IL-18的水平,另外,CSDS处理小鼠海马自噬相关蛋白Atg7、Atg5和Beclin1表达明显减少,而p62的表达则明显增加。DAPT处理能明显改善CSDS诱导的小鼠抑郁样行为,并能抑制NLRP3、ASC、caspase-1、TNF-α、IL-1β、IL-18以及p62蛋白表达的增加和Atg7、Atg5和Beclin1蛋白表达的减少。结论DAPT能够改善慢性应激诱导的小鼠抑郁样行为,其机制可能与其抑制NLRP3炎症小体激活和上调自噬功能有关。

Aim To investigate the role and mechanism of DAPT in chronic stress-induced depressive-like behavior in mice.Methods C57BL/6J mice were treated with the chronic social defeat stress(CSDS)for 10 days to establish a depression model.Mice in the drug-treated group were injected intraperitoneally with 5 mg·kg^(-1)DAPT every day.Social interaction test,sucrose preference test,open field test,forced swimming test and tail suspension test were used to evaluate the depressive-like behavior in mice.Western blot was used to detect the protein expression of NLRP3,ASC,caspase-1,TNF-α,p62,Atg7,Atg5 and Beclin1.ELISA was applied to measure the expression levels of IL-1βand IL-18.Results CSDS induced significant depressive-like behavior in mice.Meanwhile,the expression of NLRP3,ASC,caspase-1 and the levels of inflammatory cytokines TNF-α,IL-1β,IL-18 in hippocampus of mice were raised.In addition,the expressions of hippocampal autophagy-related protein Atg7,Atg5 and Beclin1 were significantly reduced in CSDS-treated mice,while the expression of p62 was markedly elevated.DAPT treatment can ameliorate CSDS-induced depressive-like behavior in mice and inhibited the increase of NLRP3,ASC,caspase-1,TNF-α,IL-1β,IL-18 and p62 protein expression and the decrease of Atg7,Atg5 and Beclin1 protein expression.Conclusions DAPT can ameliorate chronic stress-induced depressive-like behavior in mice,and the mechanism may be related to the inhibition of NLRP3 inflammasome activation and the upregulation of autophagy function.