Sestrin2 attenuates depressive-like behaviors and neuroinflammation in CUMS mice through inhibiting ferroptosis

神经炎症 化学 小胶质细胞 脂质过氧化 氧化应激 尾部悬挂试验 神经保护 免疫印迹 促炎细胞因子 药理学 细胞生物学 内分泌学 海马体 生物化学 行为绝望测验 内科学 生物 炎症 医学 抗抑郁药 基因
作者
Xinxin Ma,Jing Wang,Qiankun Quan,Huan Zhang,Ye Tian,Wenwen Wang,Ling Liu
出处
期刊:Neuroreport [Ovid Technologies (Wolters Kluwer)]
标识
DOI:10.1097/wnr.0000000000001988
摘要

Sestrin2 (SESN2) is a stress-inducible protein and acts as a neuroprotective regulator. The present study aimed to explore the antidepressant activity of SESN2 and its relevant mechanism. Depression mouse model was established by chronic unpredictable mild stress (CUMS) for a successive 5 weeks. Behaviors tests were conducted to examine depressive-like behaviors including sugar preference test, tail suspension test and open field test. The expression of SESN2 and ferroptosis-related proteins was examined by western blot. The production of cytokines was measured by ELISA. Iron deposition was assessed using Prussian blue staining and Fe2+ content was measured using commercial kits. Lipid peroxidation was evaluated by thiobarbituric acid reactive substances assay. BV-2 cells were treated with LPS to induce microglial activation, which was evaluated by the iba-1 level adopting immunofluorescence assay. The ferroptosis inducer Erastin was adopted for the pretreatment in BV-2 cells to conduct a rescue experiment. SESN2 was downregulated in CUMS-induced mice, and SESN2 overexpression dramatically ameliorated CUMS-induced depression-like behaviors. Meanwhile, SESN2 reduced the production of pro-inflammatory cytokines and iba-1 level in hippocampus of CUMS mice, as well as reducing iron deposition and lipid peroxidation, demonstrating that SESN2 reduced microglial activation, neuroinflammation and ferroptosis in CUMS mice. Similarly, SESN2 also restricted iba-1 level, pro-inflammatory cytokines production, and ferroptosis in LPS-induced BV-2 cells, which was partly reversed by additional treatment of Erastin. These findings suggest that SESN2 possesses potent antidepressant property through inhibiting ferroptosis and neuroinflammation.
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