Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation
Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation
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DOI：
10.1111/jpi.12667
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发表时间：
2020-07-17
影响因子：
10.3
通讯作者：
Li, Shupeng
中科院分区：
文献类型：
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作者：
Ali, Tahir;Rahman, Shafiq Ur;Li, Shupeng
重度抑郁症（MDD）是一种危及生命的疾病，其特征是情绪变化和高自杀率。尽管神经炎症在 MMD 中的作用已被研究，但抗抑郁药、神经炎症和自噬之间的机制相互作用仍有待研究。本研究调查了褪黑激素对 LPS 诱导的神经炎症、抑郁和自噬损伤的影响。我们的结果表明，在小鼠中，脂多糖 (LPS) 治疗会诱导抑郁样行为，并通过 ATG 基因失调引起自噬损伤。此外，LPS 处理显着增加了细胞因子（TNF α、IL-1 β、IL-6）的水平，增强了 NF-& x1d0b;B 磷酸化，引起胶质细胞（星形胶质细胞和小胶质细胞）激活，FOXO3a 表达失调，增加了氧化还原信号分子（如 ROS/TBAR）的水平，并改变了 Nrf2、SOD2 和 HO-1 的表达。褪黑激素治疗显着消除了脂多糖的作用，抑郁样行为改善、自噬相关基因表达正常化以及细胞因子水平降低就证明了这一点。此外，我们使用自噬抑制剂 3-MA 和 Ly294002 研究了自噬在 LPS 诱导的抑郁样行为和神经炎症中的作用。有趣的是，抑制剂治疗显着消除并逆转了褪黑激素的抗抑郁、促自噬和抗炎作用。本研究得出的结论是，褪黑素在 LPS 诱导的抑郁症中的抗抑郁作用可能是通过 FOXO3a 信号传导的自噬调节来介导的。
Major depressive disorder (MDD) is a life-threatening illness characterized by mood changes and high rates of suicide. Although the role of neuroinflammation in MMD has been studied, the mechanistic interplay between antidepressants, neuroinflammation, and autophagy is yet to be investigated. The present study investigated the effect of melatonin on LPS-induced neuroinflammation, depression, and autophagy impairment. Our results showed that in mice, lipopolysaccharide (LPS) treatment induced depressive-like behaviors and caused autophagy impairment by dysregulating ATG genes. Moreover, LPS treatment significantly increased the levels of cytokines (TNF alpha, IL-1 beta, IL-6), enhanced NF-& x1d0b;B phosphorylation, caused glial (astrocytes and microglia) cell activation, dysregulated FOXO3a expression, increased the levels of redox signaling molecules such as ROS/TBARs, and altered expression of Nrf2, SOD2, and HO-1. Melatonin treatment significantly abolished the effects of LPS, as demonstrated by improved depressive-like behaviors, normalized autophagy-related gene expression, and reduced levels of cytokines. Further, we investigated the role of autophagy in LPS-induced depressive-like behavior and neuroinflammation using autophagy inhibitors 3-MA and Ly294002. Interestingly, inhibitor treatment significantly abolished and reversed the anti-depressive, pro-autophagy, and anti-inflammatory effects of melatonin. The present study concludes that the anti-depressive effects of melatonin in LPS-induced depression might be mediated via autophagy modulation through FOXO3a signaling.