The effects of Kai-Xin-San in alleviating chronic social defeat stress-induced depression-like behaviors are associated with CD4+ T cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS), a traditional Chinese herbal formula which has long been clinically utilized for the management of depression. However, its precise antidepressant mechanisms and material basis remain insufficiently understood.

AIM OF THE STUDY: Investigating the underlying mechanisms of KXS in combating depression.

MATERIALS AND

METHODS

An adolescent depression model was established in C57BL/6J mice using a 10-day chronic social defeat stress(CSDS) paradigm. Following the establishment of the model, the mice received a two-week intervention with either KXS (343.7 mg/kg/day, administered orally) or fluoxetine (10 mg/kg/day, administered via intraperitoneal injection). Subsequently, the antidepressant efficacy of KXS was evaluated in the CSDS mice through a series of behavioral tests. Thereafter, Olink proteomics, high-performance liquid chromatography-mass spectrometry (HPLC-MS), flow cytometry, and immunofluorescence were employed to explore the underlying molecular mechanisms.

RESULTS

In animal experiments, KXS significantly ameliorated depression-like behaviors in CSDS mice, as evidenced by increased time spent in the central area of the open field test and in the open arms of the elevated plus maze, enhanced sucrose preference and social interaction ratio, and reduced immobility time in the forced swim test. Peripheral immunological assessments demonstrated that CSDS reduced the proportion of CD3+ T cells in the spleen, while KXS abrogated the CSDS-mediated decreases in the proportions of CD4+/CD8+ T cells and regulatory T cells (Tregs). In serum, KXS mitigated the CSDS-induced reduction in the level of 5-HT, a key metabolite in the tryptophan-kynurenine pathway. Brain tissue examination revealed that the infiltration of CD4+ T cells and macrophages at the stress state, and KXS attenuated CSDS-induced hippocampal neuronal damage, microglial activation, and astrocyte suppression. Additionally, proteomic profiling of peripheral blood also suggested that KXS exerts antidepressant effects by regulating T cell function and related signaling pathways.

CONCLUSION

KXS may ameliorate CSDS-induced depression-like behaviors through the regulation of CD4+ T cells. The underlying mechanisms involve immune-related protein expression and cellular signaling pathways, regulation of the tryptophan-kynurenine metabolic pathway, and restoration of central immune homeostasis.