Fingolimod suppressed the chronic unpredictable mild stress-induced depressive-like behaviors via affecting microglial and NLRP3 inflammasome activation
Fingolimod suppressed the chronic unpredictable mild stress-induced depressive-like behaviors via affecting microglial and NLRP3 inflammasome activation
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DOI：
10.1016/j.lfs.2020.118582
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发表时间：
2020-12-15
期刊：
影响因子：
6.1
通讯作者：
Tang, Hongmei
中科院分区：
文献类型：
--
作者：
Guo, Yuanxin;Gan, Xiaohong;Tang, Hongmei
抑郁症是现代生活方式的一个常见方面，大多数患者对目前的抗抑郁药感到不适。芬戈莫德（FTY 720）是一种鞘氨醇类似物，被批准用于治疗多发性硬化症，对中枢神经系统具有显著的神经保护作用。本研究的目的是确定FTY 720对每日暴露于慢性不可预测的轻度应激（CHNS）的大鼠的行为和认知功能的潜在治疗作用，并阐明潜在的机制。42 d的COMS造模可诱导大鼠出现糖水偏爱、强迫游泳、旷场和Morris水迷宫等抑郁样行为。从机制上讲，BRAS对海马神经元造成显著损伤，增加炎症和氧化应激，激活NF-κ B/NLRP 3轴，并使小胶质细胞极化偏向M1表型。FTY 720不仅能减轻神经元损伤和氧化应激，还能改善大鼠的抑郁样行为和认知功能。它还通过下调NLRP 3、ACS和caspase-1抑制NF-κ B活化并阻断NLRP 3炎性体组装。FTY 720还可抑制小胶质细胞M1极化标志物iNOS和CD 16，促进M2极化标志物Arg-1和CD 206。这反过来又降低了海马体中TNF-α、IL-6和IL-1 β的水平，并增加了IL-10的水平。总之，FTY 720通过抑制神经炎症保护海马神经元免受应激诱导的损伤并减轻抑郁症状。本研究为S1 P受体调节治疗抑郁症提供了理论依据。
Depression is a common aspect of the modern lifestyle, and most patients are recalcitrant to the current antidepressants. Fingolimod (FTY720), a sphingosine analogue approved for the treatment of multiple sclerosis, has a significant neuroprotective effect on the central nervous system. The aim of this study was to determine the potential therapeutic effect of FTY720 on the behavior and cognitive function of rats exposed daily to chronic unpredictable mild stress (CUMS), and elucidate the underlying mechanisms. The 42-day CUMS modeling induced depression-like behavior as indicated by the scores of sugar water preference, forced swimming, open field and Morris water maze tests. Mechanistically, CUMS caused significant damage to the hippocampal neurons, increased inflammation and oxidative stress, activated the NF-kappa B/NLRP3 axis, and skewed microglial polarization to the M1 phenotype. FTY720 not only alleviated neuronal damage and oxidative stress, but also im proved the depression-like behavior and cognitive function of the rats. It also inhibited NF-kappa B activation and blocked NLRP3 inflammasome assembly by down-regulating NLRP3, ACS and caspase-1. Furthermore, FTY720 inhibited the microglial M1 polarization markers iNOS and CD16, and promoted the M2 markers Arg-1 and CD206. This in turn reduced the levels of TNF-alpha, IL-6 and IL-1 beta, and increased that of IL-10 in the hippocampus. In conclusion, FTY720 protects hippocampal neurons from stress-induced damage and alleviates depressive symptoms by inhibiting neuroinflammation. Our study provides a theoretical basis for S1P receptor modulation in treating depression.