Insights into the Prevention and Treatment of Depression with Famous TCM Prescription Xiaoyaosan

Traditional Chinese medicine (TCM) prescription is a formula established based on clinical disease pattern differentiation, following the therapeutic principles and methods of TCM, in accordance with the compatibility rules of TCM as "Principals, associates, adjuvants and messengers". As the main method of TCM to treat diseases, TCM prescription is also the main embodiment of the philosophical speculation of TCM pattern differentiation and treatment. The elaboration of the mechanism of action and the material basis of traditional Chinese medicine prescription is of great significance to understanding disease pathogenesis and the revelation of therapeutic targets, embodying the scientific connotation of TCM. Xiaoyaosan (XYS) comes from the "Taiping Huimin Heji Bureau Prescription" in the Song Dynasty. As a representative prescription of TCM for the treatment of emotional diseases attributed to the pattern of liver depression and spleen deficiency, such as depression and anxiety, it has been used for thousands of years and has significant antidepressant and anti-anxiety effects. Revealing the antidepressant and anti-anxiety pharmacodynamic mechanism of XYS and elaborating the material basis of XYS are of great significance for the research and treatment of emotional disorders and the elaboration of the scientific connotation of the correlation between Classical Prescription and pattern in TCM. By establishing three different depression models, including chronic unpredictable mild stress, chronic immobilized stress, and chronic restraint stress, combined with clinical research, network pharmacological analysis, ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS), 16S rDNA high-throughput method and molecular biology, we have revealed the antidepressant and anxiolytic mechanism of XYS and the material basis of its pharmacodynamics from multiple levels. Our results show that XYS could target the central nervous system (CNS), liver, and intestinal tract to exert its medicinal effect. In the CNS, XYS has been shown to interfere with the hypothalamo-pituitary-adrena axis, glial fibrillary acidic protein and Glu-NMDA receptors; regulate the expression levels of tryptophan hydrogenase 2 and indoleamine 2,3-dioxygenase 1 in the hippocampus; regulate the glutamate/glutamine cycle and the glutamate transporter GLT-1 in the hippocampus; downregulate tumour necrosis factor- /janus kinase 2-signal transducer and activator of transcription pathway in hippocampus; improve the function of astrocytes and excitatory amino acid transporters in prefrontal cortex; regulate nesfatin-1-oxytocin-proopiomelanocortin neural pathway in hypothalamus; regulate mRNA expression of related anabolic enzymes in hippocampus and amygdala, for antidepressant/anti-anxiety effects. In the periphery, XYS has been revealed to improve the abnormal levels of insulin, blood glucose, cholesterol, low-density lipoprotein and high-density lipoprotein in plasma by regulating the expression of SHIP2 in the liver. In the intestinal tract, XYS has been found to treat mood disorders by regulating the abundance of intestinal flora and reducing intestinal permeability. The joint analysis of network pharmacological analysis and UPLC-Q/TOF-MS showed that paeoniflorin, quercetin, luteolin, acacetin, aloe-emodin, Glyasperin C, kaempferol in XYS could play an antidepressant effect by regulating the pathways related to metabolism, neuroendocrine function and neuroimmunity, and affecting the expression of AKT1, TP53 and VEGFA genes. In summary, we have collected into this book the representative studies published by Prof. Chen’s laboratory in 2020 and before. These studies reveal the pharmacodynamic mechanism of XYS for anti-depression and anti-anxiety, as well as clarify the material basis of XYS, which could serve as a practical reference value for researching and treating stress-related emotional disorders.