Tao-Hong-Si-Wu Decoction improves depressive symptoms in model rats via restorations of neural transmitters and ameliorations of BDNF-CREB-arginase I axis disorders

Abstract Background Depressive disorder (DD) has become a global health problem. Applications of Chinese medicine have been demonstrated to be potential in the treatment of DD. Tao-Hong-Si-Wu decoction (TSD), a traditional Chinese medicine formula is widely used to treat ameliorate anemia, liver and heart dysfunctions, and inflammation. Such symptoms are also associated with DD. Hence, our initial hypothesis was to observe and explore the targets of the effect of TSD on DD. Methods The DD model was established by chronic unpredictable mild stress (CUMS) in rats. The measurements of body weight and behavioral tests were performed to confirm the success of modeling and observe the effect of TSD on the model animals. A gas-chromatography coupled with mass spectrometry (GC-MS)-based metabolomic analysis was conducted to reveal the metabolic characteristics related to the curative effect of TSD. Serum serotonin and arginase I (Arg I), which are associated with the key feature metabolites responsible for the effect of TSD on depression, were assessed by an ELISA assay. Proteins in the Brain-derived neurotrophic factor (BDNF)/ Tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling, which lead to the regulations of Arg I, were analyzed using Western blot assay. Results Body weight losses and increased immobility durations in the behavioral tests were observed in the CUMS rats while such features were attenuated in the TSD-treated rats. General decreases in serum amino acids and energetic metabolites were found in CUMS rats. Significant increased ornithine and urea, the products of arginase degradation, were also characterized in the DD-mimicked rats. These metabolic dysregulations were reversed in the TSD-treated groups. Upregulated Arg I and downregulated serotonin were observed in the model group but the dysregulations were improved in the TSD-treated groups. Compared with the blank control, lower expressions of BDNF, TrkB, extracellular signal-regulated kinases (ERK), p-ERK, and CREB were found in the hippocampus of CUMS rats. Expressions of the proteins were restored in all the TSD-treated groups. Conclusions TSD improves depression-like symptoms in CUMS rats, which may be primarily related to its effect both on enhancing the release of neural transmitters such as glycine and serotonin and on the improvement of disorders of the BNDF-CREB-Arg I axis.