Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats

Major depressive disorder is two times more prevalent in females than males. Further, immune system dysfunction has been shown to contribute to the development of depression, with previous studies consistently reporting chronic low-grade inflammation in depressed individuals. Not surprisingly, the immune system dysfunction associated with depression appears to be sex specific. As such, while anti-inflammatory drugs have shown antidepressant effects in preclinical studies, the sex differences in these effects are seldomly investigated. Thus, this study sought to determine the sex-specific antidepressant and immune modulatory effects of dimethyl fumarate (DMF) treatment. DMF is a drug that activates the protein nuclear factor erythroid 2-related factor 2 to initiate anti-inflammatory signaling pathways. Here, male and female rats were exposed to 8 weeks of chronic stress while receiving daily DMF treatment. Subsequently, their expression of depression- and anxiety-like behaviours, as well as learning and memory deficits were assessed. Changes in the levels of an inflammatory marker in the brain and alterations in gene expression were also evaluated. DMF treatment had antidepressant effects in male rats only but did not have anti-anxiety effects in either sex. The learning and memory deficits in both sexes were rescued with DMF treatment. Notably, chronic stress only increased inflammatory marker levels in male rats, which was prevented by DMF treatment. Additionally, DMF normalized several of the sex-specific gene alterations induced by chronic stress, with many of the male-specific genes relating to inflammatory processes. These data suggest that anti-inflammatory drugs may be an effective antidepressant treatment in males.重度抑郁症（Major Depressive Disorder）在女性群体中的患病率为男性的两倍。现有研究证实，免疫系统功能失调参与抑郁症的发生发展，既往研究均一致报道抑郁症患者存在慢性低度炎症状态。无独有偶，与抑郁症相关的免疫系统功能失调呈现出性别特异性。鉴于此，尽管抗炎药物在临床前研究中已展现出抗抑郁功效，但此类药物抗抑郁效应的性别差异却鲜有研究涉及。因此，本研究旨在探究富马酸二甲酯（dimethyl fumarate, DMF）干预的性别特异性抗抑郁及免疫调控效应。富马酸二甲酯是一种可激活核因子红细胞2相关因子2（nuclear factor erythroid 2-related factor 2），进而启动抗炎信号通路的药物。本实验中，雌雄大鼠每日接受富马酸二甲酯干预的同时，暴露于8周慢性应激环境。随后，研究人员对大鼠的抑郁样、焦虑样行为表现以及学习记忆功能缺陷情况进行了评估，同时还检测了大鼠脑部炎症标志物水平的变化以及基因表达的改变。富马酸二甲酯仅在雄性大鼠中展现出抗抑郁效应，且对两种性别的大鼠均无显著抗焦虑作用。富马酸二甲酯干预可改善两种性别大鼠的学习记忆功能缺陷。值得注意的是，慢性应激仅会升高雄性大鼠的脑部炎症标志物水平，而该现象可被富马酸二甲酯干预阻断。此外，富马酸二甲酯可使慢性应激诱导的多种性别特异性基因表达异常恢复正常，其中多数雄性特异性基因与炎症过程相关。上述实验结果表明，抗炎药物或可成为男性群体的有效抗抑郁治疗手段。