Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Psychology, The Fourth Affiliated Hospital of Xinjiang Medical University, Xinjiang, China.
Phytother Res. 2022 Aug;36(8):3335-3351. doi: 10.1002/ptr.7518. Epub 2022 Jun 9.
Major depressive disorder (MDD) is a severe life-threatening disorder with increasing prevalence. However, the mechanistic interplay between depression, neuroinflammation, and autophagy is yet to be demonstrated. This study investigated the effect of Oridonin on CUMS-induced depression, neuroinflammation, and autophagy impairment. Male 4-week-old Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS), some of which were injected with Oridonin, fluoxetine (FLX), or their combination at different durations of CUMS. CUMS significantly increased the levels of cytokines (IL-1β, IL-18, and caspase-1), reduced autophagy-related protein levels (Beclin-1, p62, Atg5, and LC3B), and caused microglia cells activation. Oridonin prevented and reversed the depressive-like behavior. Furthermore, it has a stronger and longer-lasting antidepressant effect than FLX. And the antidepressant effect of Oridonin in combination with fluoxetine was greater than that of high-dose fluoxetine alone. In addition, Oridonin significantly normalized autophagy-related protein levels, and reduced levels of cytokines by blocking the interaction between NLRP3 and NEK7. Similarly, Oridonin abolished levels of cytokines and reversed autophagy impairment in LPS-activated BV2 cells. All these results supported our hypothesis that Oridonin possesses potent anti-depressive action, which might be mediated via inhibition of neuroinflammation and autophagy impairment by blocking the interaction between NLRP3 and NEK7.
重度抑郁症（MDD）是一种严重的危及生命的疾病，其患病率正在不断增加。然而，抑郁症、神经炎症和自噬之间的机制相互作用尚未得到证实。本研究旨在探讨冬凌草甲素对 CUMS 诱导的抑郁、神经炎症和自噬损伤的影响。雄性 4 周龄 Sprague-Dawley 大鼠接受慢性不可预测轻度应激（CUMS），其中一些大鼠在不同的 CUMS 持续时间内注射冬凌草甲素、氟西汀（FLX）或两者的组合。CUMS 显著增加了细胞因子（IL-1β、IL-18 和 caspase-1）的水平，降低了自噬相关蛋白水平（Beclin-1、p62、Atg5 和 LC3B），并导致小胶质细胞激活。冬凌草甲素可预防和逆转抑郁样行为。此外，其抗抑郁作用比 FLX 更强、持续时间更长。并且冬凌草甲素与氟西汀联合使用的抗抑郁效果大于单独使用高剂量氟西汀的效果。此外，冬凌草甲素通过阻断 NLRP3 和 NEK7 之间的相互作用，显著恢复了自噬相关蛋白水平，并降低了细胞因子水平。类似地，冬凌草甲素消除了 LPS 激活的 BV2 细胞中的细胞因子水平并逆转了自噬损伤。所有这些结果都支持我们的假设，即冬凌草甲素具有强大的抗抑郁作用，可能通过阻断 NLRP3 和 NEK7 之间的相互作用来抑制神经炎症和自噬损伤来介导。
