Objective

2

To predict the molecular mechanism of Erxian decoction and Wenshen prescription （modified Erxian decoction） in the treatment of depression based on network pharmacology and explore the feasibility of Wenshen prescription in the treatment of depression by comparing the efficacy and mechanism of the two decoctions based on a depression model induced by maternal separation combined with chronic restraint stress.

Method

2

Active components and targets of Erxian decoction and Wenshen prescription were collected through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） and Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine （BATMAN-TCM）. Targets related to depression were screened out from databases such as GeneCards， Online Mendelian Inheritance in Man database （OMIM）， and DrugBank. Common targets of drugs and disease were obtained and imported to Cytoscape 3.8.2 to plot the drug-active component-target-disease network. STRING platform was used to construct a protein-protein interaction （PPI） network and core targets and related core components were screened out. Gene Ontology （GO） enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） functional enrichment analysis were performed on common targets through Metascape platform. The depression model was induced in mice by maternal separation combined with chronic restraint stress. From the 21st day of maternal separation （PD21） to the 111th day of restraint stress completion （PD111）， mice were fed with the diet mixed with Erxian decoction or Wenshen prescription for intervention. The depressive state of mice was evaluated according to the sucrose preference test， tail suspension test， open field test， and elevated O-maze test. The expression of ionized calcium-binding adapter molecule 1 （Iba1） in the microglia was observed by immunohistochemistry （IHC）. Western blot and Real-time fluorescence-based quantitative polymerase chain reaction （Real-time PCR） were used to detect the expression levels of protein kinase B1（Akt1）， brain-derived neurotrophic factor （BDNF）， postsynaptic density-95 （PSD95）， and synaptophysin （Syn）.

Result

2

A total of 126 and 118 targets of Erxian decoction and Wenshen prescription in the treatment of depression were screened out， with only eight more targets of Erxian decoction than Wenshen prescription. The two decoctions shared the same core targets， mainly including Akt1， interleukin-6 （IL-6）， interleukin-1

β

（IL-1

β

）， and tumor necrosis factor-α （TNF-

α

）. KEGG pathway enrichment analysis predicted that Erxian decoction and Wenshen prescription mainly treated depression through the phosphatidylinositol-3 kinase （PI3K）/Akt signaling pathway， mitogen-activated protein kinase （MAPK） signaling pathway， and neuroactive ligand-receptor interaction pathway. Animal experiments showed that compared with the results in the model group， Erxian decoction and Wenshen prescription could up-regulate the sucrose preference index， prolong the time spent in the central zone， increase the number of crossings， prolong the time spent in opened arm， increase the number of crossings in the opened arm， elevate the expression levels of p-Akt1， BDNF， PSD95， and Syn （

P

<

0.05，

P

<

0.01）， shorten the immobility time of tail suspension， and reduce the expression level of Iba-1 in the hippocampal microglia （

P

<

0.05，

P

<

0.01）. No significant difference between the two decoctions was found.

Conclusion

2

Under the pathogenesis and syndrome law of depression dominated by kidney yang deficiency， Wenshen prescription modified from Erxian decoction is feasible in the treatment of depression. The mechanism may be attributed to the fact that both decoctions can improve neuroinflammation and synaptic plasticity in the hippocampus by affecting Akt1， IL-1

β

， IL-6， TNF-

α

， and other core targets and regulating the PI3K/Akt， MAPK， and neuroactive ligand-receptor interaction signaling pathways.