Network pharmacology is a method to predict the possibility of drug treatment for diseases by searching for drug-disease shared genes and finding gene enrichment pathways, which are then confirmed by available experimental evidence. And molecular docking can predict the binding power of active ingredients to target proteins, which further confirms the therapeutic effect of drugs. The use of these techniques has largely solved the great challenges posed to research due to the multi-component and multi-target nature of TCM. Therefore, we used network pharmacology and molecular docking to reveal the possible mechanism of action of Gan-Mai-Da-Zao decoction against PSD.
In our study, the core active ingredients were screened in the “D-H-C-T” network, including quercetin, luteolin, kaempferol, naringenin, isorhamnetin, etc. In recent years, it has been found that flavonoids have significant effects on the central system, with neuroprotective, antidepressant, and anxiolytic effects . In our study, quercetin is derived from Glycyrrhiza uralensis Fisch. and Ziziphus jujuba Mill. A relevant animal study confirmed that quercetin could reverse the stress-induced depression and anxiety in the mice . Besides, it’s evidenced that quercetin exerts anti-depressant effects through anti-oxidant, anti-inflammatory, decreasing cytotoxicity, and increasing 5-hydroxytryptamine levels . Luteolin is derived from Triticum aestivum L. It’s reported that luteolin showed an anti-depressant effect via suppressing the endoplasmic reticulum , inhibiting and downregulating plasma membrane monoamine transporter (PMAT, Slc29a4) . The study also found that luteolin may improve cognitive performance by inhibiting microglial activation and neuroinflammation in older mice . Kaempferol, naringenin, and isorhamnetin are all derived from Glycyrrhiza uralensis Fisch. Kaempferol promoted the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein in hippocampal tissue of aged rats in a chronic stress depression model, which resulted in neuroprotection and improved depression-like behavior . Naringenin is a flavonoid compound with strong anti-oxidant and anti-inflammatory effects. The literature evidenced that naringin may produce functional behavioral effects through enhancement of cholinergic transmission, antioxidant defense systems, inhibition of lipid peroxidation and nitrosative processes . The application of isorhamnetin potentiated the nerve growth factor (NGF) induced neurite outgrowth. In parallel, the expression of neurofilaments was markedly increased in the co-treatment of NGF and isorhamnetin in the cultures. This suggested that isorhamnetin might be used to some extent in the treatment of neurodegenerative diseases, including Alzheimer's disease and depression . These important active ingredients are all sourced from Gan-Mai-Da-Zao decoction, and multiple active ingredients work together to exert their effects in the treatment of PSD.
In addition, a total of 19 core targets of Gan-Mai-Da-Zao decoction for PSD were screened in the PPI network, including AKT1, STAT3, TP53, CTNNB1, CDKN1A, ESR1, VEGFA, MAPK1, MAPK3, CASP8, CCND1, MAPK14, RELA, TNF, EGFR, FOS, JUN, CXCL8, STAT1. Among them, EGFR is highly expressed in a variety of malignancies, and depression is common in oncology patients, being four times more prevalent than in the general population [41, 42]. Meanwhile, it’s also found that EGFR mutant non-small cell lung cancer produced depression by mediating inflammatory factors . Depressant-like behavior was induced by forced swimming, and MAPK1 was overexpressed in the hippocampus to lead anti-depressant effect . It’s reported that estrogen-regulated neurotransmitter conversion and thus produced anti-depressant effects. It’s thought that the biological function of estrogen is largely mediated by intracellular activation of its primary receptors, estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2). Thus, genetic variation in ESR played an important role in the susceptibility of women to depression [45, 46]. STAT3 is expressed in both hippocampal neurons and glial cells and is closely related to neurodegenerative diseases. It was demonstrated that pharmacological treatment of PSD and improvement of depressive state may be related to the inhibition of JAK2/STAT3 signaling pathway-related gene and protein expression to promote the neural remodeling in the hippocampal .
Among the 20 pathways screened by KEGG enrichment analysis, some of them are closely related to PSD, including TNF and Toll-like receptor signaling pathways. The immune-inflammatory response is one of the important pathogenic mechanisms of PSD. Elevation of various inflammatory biomarkers such as IL-6, TNF-α, increased high sensitive C-reactive protein (CRP) concentration was found to be present in mild to moderate depressive patients six months following stroke [48, 49]. It has been shown that the improvement in depression in rats under acupuncture intervention may be closely related to the Toll-like receptor pathway and TNF signaling pathway enriched by significantly downregulated differentially expressed genes in the hippocampus, frontal lobes, and pituitary gland of rats . Also, there are pathological mechanisms such as neuronal apoptosis and nerve growth disorders involved in some pathways that also play an important role in the development of PSD. The efficacy of current antidepressants has been linked to the Ras signaling pathway, which may be involved in the onset and development of depression-related disorders by indirectly affecting neurotrophic factors or directly affecting neuroplasticity . Furthermore, antidepressants not only upregulate cAMP levels in receptor cells but also activate protein kinase A (PKA) to phosphorylate PKA, which then activates the cAMP-response element-binding protein (CREB) signaling pathway, altering functional protein activity and gene expression patterns to form new synapses, thus exerting antidepressant effects .