Jiao-tai-wan and its bioactive constituent jatrorrhizine exert antidepressant effects via the STING pathway

Ethnopharmacological relevance: Jiao-tai-wan (JTW) is a classical traditional Chinese medicine formula that has long been used to treat insomnia. Recent pharmacological studies have highlighted its potential antidepressant effects. However, its role in regulating neuroinflammation associated with depression and the underlying mechanisms remains unclear.

Aim of the study: To elucidate the therapeutic mechanisms of JTW in depression and to identify its bioactive constituents.

Materials and methods: A chronic restraint stress (CRS) model was established in C57BL/6J mice, which were administered saline, low-dose JTW (2.4 g/kg/day), or high-dose JTW (4.8 g/kg/day) via gavage for 21 days. LPS-stimulated BV2 cells were utilized as an in vitro neuroinflammatory model. Molecular docking identified jatrorrhizine (JAT) as the key anti-inflammatory component of JTW. The in vitro study was conducted in two phases. Phase I included four groups: Control, LPS, LPS + low-dose JAT (LJAT), and LPS + high-dose JAT (HJAT). Phase II involved BV2 cells transfected with si-NC or si-STING, assigned to Control, LPS, and LPS + JAT groups. In vivo, CRS mice were treated with either JAT or C176, a STING inhibitor. Behavioral assessments, histopathological analysis, and cytokine measurements in serum and hippocampal tissues were performed. Mechanistic investigations using immunofluorescence, RT-qPCR, and Western blot were conducted to examine STING pathway activity in both BV2 cells and hippocampal tissues.

Results: JTW alleviated depressive-like behaviors in CRS mice by inhibiting microglial activation, reducing neuroinflammation, and protecting hippocampal neurons, effects associated with suppression of the STING signaling pathway. In vitro, JAT mitigated LPS-induced cytotoxicity in BV2 cells. Integrated in vivo validation confirmed JAT as the principal bioactive constituent mediating the antidepressant effects of JTW through inhibition of the STING pathway.

Conclusion: JTW could exert antidepressant effects by modulating neuroinflammation via inhibition of the STING pathway, with JAT identified as its key active constituent. The results provide pharmacological evidence supporting the use of traditional Chinese medicine in the treatment of depression.

Depression; Jatrorrhizine; Jiao-tai-wan; Neuroinflammation; STING pathway.