[Zhizichi Decoction alleviates depression-like behaviors in rats exposed to chronic unpredictable mild stress by modulating tryptophan metabolism and the BDNF signaling pathway].

OBJECTIVES

To evaluate the regulatory effects of Zhizichi Decoction on tryptophan metabolism, inflammation, and neurotrophic factor-related signaling pathways and its potential antidepressant effects in a rat model of depression induced by chronic unpredictable mild stress (CUMS).

METHODS

Adult male SD rat models of CUMS-induced depression were randomized into CUMS model group, fluoxetine group, low-dose Zhizichi Decoction group (LZZCD), and high-dose Zhizichi Decoction group (HZZCD) (n=10), with another 10 normal rats as the control group. After modeling, the rats received daily drug interventions via gavage for 4 weeks. Forced swimming test, tail suspension test, and voluntary activity recording were used to assess depressive-like behaviors of the rats. HE staining, Western blotting and ELISA were used to evaluate the changes in brain tissue pathologies, tryptophan metabolism, neurotransmitter levels, inflammation and brain-derived neurotrophic factor (BDNF)-related pathways of the rats.

RESULTS

The rat models with CUMS showed significantly increased immobility and reduced swimming and struggling time. Both fluoxetine and Zhizichi Decoction at the two doses markedly alleviated depressive-like behaviors of the rat models, and high-dose Zhizichi Decoction produced the strongest ameliorating effect. Zhizichi Decoction treatment reduced brain injury scores of the rats, upregulated TPH2 and downregulated IDO, KMO, and MAO-A expressions in the hippocampus, causing also inhibition of the NF‑κB/NLRP3 pathway and increased hippocampal expressions of TrkB, p-CREB, p-AKT, and p-ERK. ELISA results demonstrated that Zhizichi Decoction treatment increased Trp, 5-HT, and 5-HIAA levels, decreased the levels of Kyn and inflammatory cytokines, and upregulated BDNF expression in the hippocampus of the rat models.

CONCLUSIONS

Zhizichi Decoction alleviates depressive-like behaviors and brain pathologies in CUMS rats by regulating tryptophan metabolism, enhancing synthesis and reducing degradation of neurotransmitters, inhibiting inflammatory response, and upregulating the BDNF signaling pathway.