Integrated Network Pharmacology Analysis and Experimental Validation to Investigate the Mechanism of Zhi-Zi-Hou-Po Decoction in Depression

Abstract

Zhi-Zi-Hou-Po Decoction (ZZHPD) is a well-known traditional Chinese medicine (TCM) that has been widely used in depression. However, the antidepressant mechanism of ZZHPD has not yet been fully elucidated. The purpose of this study was to explore the pharmacological mechanisms of ZZHPD acting on depression by combining ultra flow liquid chromatography with quadrupole time-of-flight mass spectrometry (UFLC-Q-TOF/MS) and network pharmacology strategy. The chemical components of ZZHPD were identified using UFLC-Q-TOF/MS, while the potential drug targets and depression-related targets were collected from databases on the basis of the identified compounds of ZZHPD. Protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were used to unravel potential antidepressant mechanisms. The predicted antidepressant targets from the pharmacology-based analysis were further verified in vivo. As a result, a total of 31 chemical compounds were identified by UFLC-Q-TOF/MS; 514 promising drug targets were mined by using the Swiss Target Prediction; and 527 depression-related target genes were pinpointed by the GeneCards and OMIM databases. STRING database and Cytoscape’s topological analysis revealed 80 potential targets related to the antidepressant mechanism of ZZHPD. The KEGG pathway analysis revealed that the antidepressant targets of ZZHPD were mainly involved in dopaminergic synapse, serotonin synapse, cAMP, and mTOR signaling pathways. Furthermore, based on the animal model of depression induced by chronic corticosterone, the regulatory effects of ZZHPD on the expression of MAOA, MAOB, DRD2, CREBBP, AKT1, MAPK1, HTR1A, and GRIN2B mRNA levels as well as the cAMP signaling pathway and monoaminergic metabolism were experimentally verified in rats. Our study revealed that ZZHPD is expounded to target various genes and pathways to perform its antidepressant effect.

Uncovering the Potential Mechanisms of Coptis chinensis Franch. for Serious Mental Illness by Network Pharmacology and Pharmacology-Based Analysis

“…DA receptors of dopaminergic synapses and 5-HT receptors of serotonergic synapses are predicted targets and biological pathways for the efficacy of C. chinensis Franch. Recent network pharmacology studies on TCM treatment of SMIs 79,80 also found that the obtained targets were enriched in dopaminergic synapses and serotonergic synapses. These predicted results support each other, revealing the involvement of these pathways in the treatment of SMIs, and reflecting the commonality of the pathogenesis among SMIs.…”

Potential Anti-Depressive Effects and Mechanisms of Zhi-Zi Hou-Po Decoction Using Behavioral Despair Tests Combined With in Vitro Approaches

“…ZHD-EE samples were prepared according to a previous developed method in our laboratory ( Bai et al, 2021 ). And the ZHD-WE was prepared by the water-boiling method.…”

“…The method for the determination of seven compounds (genipin 1-gentiobioside, geniposide, naringin, hesperidin, neohesperidin, honokiol, and magnolol) in ZHD-WE and ZHD-EE was described in the light of the method previously developed by our laboratory ( Bai et al, 2021 ). The results shown that the baseline separation of these ZHD-WE and ZHD-EE was achieved under optimum conditions ( Supplementary Figure S1 ).…”

“…It was originally described in Treatise on Febrile and Miscellaneous Diseases and composed of Gardenia jasminoides J. Ellis, Magnolia officinalis Rehd. et Wils., and Citrus × aurantium L. In previous study, we have proved the antidepressant effect of ZHD-EE in the animal depressive model induced by corticosterone by regulating the cAMP signaling pathway and monoaminergic metabolism ( Bai et al, 2021 ). There is no comparative study on the antidepressant effects of ZHD-WE and ZHD-EE.…”

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“…Furthermore, we focused on exploring the neuroprotective effects of ZHD-EE on the corticosterone-induced apoptosis of PC12 cells and discussed whether the resulting neuroprotection was due to upregulation of the expression of the BDNF and restoring the balance of the Bcl-2/Bax apoptotic pathway. ZHD-EE samples were prepared according to a previous developed method in our laboratory (Bai et al, 2021). And the ZHD-WE was prepared by the water-boiling method.…”