Oridonin relieves depressive-like behaviors by inhibiting neuroinflammation and autophagy impairment in rats subjected to chronic unpredictable mild stress

Abstract Background: Major depressive disorder (MDD) is a common, chronic, and severe life-threatening disorder with increasing prevalence . Although neuroinflammation is associated with the etiology of depression, the mechanistic interplay between depression, neuroinflammation, and autophagy is yet to be demonstrated. This study investigated the effect of Oridonin on CUMS-induced neuroinflammation, depression, and autophagy impairment. Methods: Male 4-week-old Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) for 4 and 6 weeks respectively, some of which were injected with Oridonin, fluoxetine (FLX) or their combination at different durations of CUMS. After CUMS procedure, sucrose preference test and Forced swim test were used to evaluate depressive-like behaviors. Concomitant neuroinflammation changes and autophagy impairments were examined in the hippocampus. Reults: In this study, we found that chronic stress resulted in depressive-like behaviors and caused neuroinflammation and autophagy impairment. In particular, CUMS treatment significantly increased the levels of cytokines (IL-1β, IL-18 and Caspase-1), reduced autophagy-related protein levels (Beclin-1, p62, Atg5 and LC3B), caused microglia cells activation. Oridonin treatment can prevent and reverse the depressive-like behavior induced by CUMS in prophylactic and therapeutic administration, but there is ceiling effect in the treatment process. Furthermore, 10mg/kg dose of Ori has a stronger and longer lasting antidepressant effect than the 10mg/kg dose of fluoxetine. And the antidepressant effect of Ori in combination with fluoxetine was greater than that of high-dose fluoxetine alone. In addition, Ori treatment significantly normalized autophagy-related protein levels, and reduced levels of cytokines via blocking the interaction between NLRP3 and NEK7. Further, we investigated the role of autophagy in LPS-activated BV2 cells and levels of cytokines. Similarly, Oridonin treatment abolished and reversed levels of cytokines and autophagy-related protein levels . Conclusions: All these results supported our hypothesis that Ori possesses potent anti-depressive action, which might be mediated via inhibition of neuroinflammation and autophagy impairment through blocking the interaction between NLRP3 and NEK7.