Hydrogen sulphide alleviates depression-like behaviors by suppressing the hippocampal necroptosis-neuroinflammation-KP imbalance axis

Background We have previously demonstrated that hydrogen sulfide (H 2 S) is sufficient to attenuate depressive-like behavior induced by chronic unpredictable mild stress (CUMS), but its underlying mechanisms remain largely unknown. It is well known that necroptosis is a trigger of inflammation and neuroinflammation-induced kynurenine pathway (KP) imbalance is the main pathogenesis of depression. Meanwhile, H 2 S plays a pivotal role in the inhibition of inflammatory pathways. Hence, the present study sought to investigate whether the antidepressant effect of H 2 S is attributable to the inhibition of the axis of hippocampal necroptosis-neuroinflammation-KP imbalance. Methods The depression model of Sprague-Dawley (SD) rats was established by CUMS for four consecutive weeks. The expressions of necroptosis-related protein and KP-related protein were evaluated by Western blotting (WB). The levels of inflammatory factors were measured by enzyme-linked immunosorbent assay (ELISA). The hippocampal metabolites of tryptophan were determined by LC-MS/MS. Results In this study, we found that H 2 S was capable of inhibiting necroptosis and neuroinflammation and correcting KP imbalance in the hippocampus of CUMS-exposed rats. The enhancement of necroptosis via overexpressing RIPK3 reversed the antagonistic role of H 2 S in the depressive-like behaviors of CUMS-exposed rats and the inhibitory effects of H 2 S on necroptosis, neuroinflammation, and KP imbalance in the hippocampus of CUMS-exposed rats. Furthermore, overexpressing indoleamine 2,3-dioxygenase 1 (IDO1) abolished the correcting effect of H 2 S on hippocampal KP imbalance and the attenuating effect of H 2 S on depressive-like behaviors in the CUMS-exposed rats. Conclusion The antidepressant-like role of H 2 S is achieved by negatively regulating the axis of necroptosis-neuroinflammation-KP imbalance in the hippocampus.