Serum Pharmacology Combined with Network Pharmacology Reveals the Effects and Mechanisms of Ganmai Dazao Decoction in the Treatment of Depression.

Ganmai Dazao Decoction (GMZ) is a famous classic traditional Chinese medicine compound prescription for the treatment of depression and has a good clinical effect. However, its specific components and molecular mechanisms are still unclear. The chronic unpredictable mild stress (CUMS) mouse model was employed in this study, and the antidepressant effect of GMZ was evaluated via behavioral and serum corticosterone level assessment. Chemical components in GMZ water decoction, drug-containing serum, and drug-containing brain homogenate were detected by ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (LC-TOF-MS). GO and KEGG analyses were performed on the intersecting targets of drugs and diseases to predict the antidepressant pharmacological mechanism of GMZ. Potential active components of GMZ were screened by molecular docking. The predicted targets were further validated for their role in and to verify the pharmacological mechanism of GMZ through in vitro and in vivo experiments. The CUMS mouse model was successfully established and GMZ (7 and 14 g/kg) was proven to have an antidepressant effect in this study. By using LC-TOF-MS analysis, 36 chemical components were identified in GMZ water decoction, 33 and 7 chemical components were identified in mouse serum and brain homogenates, respectively. There were 237 intersection targets between drug active targets and disease targets, and 48 core targets were further screened by the STRING database. GO and KEGG analyses indicated that GMZ regulated cAMP signaling pathway to achieve an antidepressant effect. Three potential components of GMZ were screened out by molecular docking, including Glyasperin C, Naringenin, and Scopoletin. The regulation effects of GMZ and its active components on the cAMP-PKA-CREB-BDNF signaling pathway were confirmed by in vitro and in vivo experiments. Our research proved that GMZ exerts an antidepressant effect through regulating the cAMP signaling pathway based on the model of "pharmacodynamics-serum pharmacology-network pharmacology-mechanism verification". This model could be a prospective approach to exploring the pharmacological mechanisms of traditional Chinese medicine.