Network pharmacology and experimental verification to explore the anti-depression mechanism of Ganmaidazao-Shanzha Decoction

To explore the pharmacological mechanism of the antidepressant-like effects of Ganmaidazao-Shanzha Decoction (GMS) through network pharmacological analysis and experimental verification. The active ingredient and the target of action related to depression were clarified by searching the herb group identification, GeneCards and Drugbank, Pharmgkb, CTD, Disgenet databases, and the protein interaction relationship was obtained by using the String database, and the protein interaction network map was constructed by using Cytoscape software. We also performed gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of key targets of the antidepressant-like effects of GMS and predicted the core targets and pathways. Furthermore, BDNF pathway which involved in antidepressant-like effect of GMS was validated by mice model to validate the results of partial network pharmacology analysis. A total of 276 active ingredients and 1142 related targets of action were retrieved from GMS, and a total of 2164 common targets were obtained by mapping the obtained depression disease targets and drug targets. Protein interaction network analysis indicated that targets including AKT1, SRC, HSP90AA1, PRKACA, PIK3R1, PIK3CA and other targets may be the core targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that the treatment of depression by GMS might include phosphorylation, synaptic plasticity and growth factor stimulus processes, and the signaling pathways might include AGE-RAGE signaling pathway in diabetic complications, Neurotrophin signaling pathway, and PI3K-Akt signaling pathway. The results of the in vivo tests showed that GMS could reverse the depressive behaviors induced by corticosterone in mice. The activity of GMS against depression was found to be mediated through neurotrophin signaling pathway by targeting the Brain-derived neurotropic factor (BDNF) signaling proteins and downstream synaptic proteins, promoting the c-fos positive cell restoration and finally leading to hippocampal neurogenesis in age difference. Through the application of network pharmacology and in vivo validation experiments, this study revealed the active components and the potential targets of GMS for the treatment of depression, providing a theoretical basis for the research and clinical application of GMS.