Abstract
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.