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Ethnopharmacological relevance: Clinical research and basic scientific experiments have shown that modified Xiao Yao San (MXYS) has antidepressant effects, whose system mechanism however has not been thoroughly characterised.
Aim of the study: This research was aimed at evaluating the treatment effects of Xiao Yao San on chronic unpredictable mild stress (CUMS)-induced depressive mice and exploring underlying mechanisms.
Materials and methods: Whether MXYS has effects on depression was investigated via the depressive behaviors of mice, electron microscopy, real-time quantitative polymerase chain reaction (RT-qPCR), Western blot analysis, immunofluorescence (IF) staining and the stereotaxic injection of adeno-associated viruses (AAVs). In addition, network pharmacology was applied to predict relevant molecular targets and possible mechanisms and perform further in vivo validation.
Results: MXYS is effective in ameliorating the depression-like symptoms of CUMS mice. It can stimulate autophagosome formation, activate the expression of microtubule-associated protein 1 light chain 3 (LC3B), autophagy-related gene 5 (Atg5), Atg7 and neuron-specific nuclear protein (NeuN), and decrease the protein expression sequestosome 1 (SQSTM1/p62). The autophagy-upregulating effect of Xiao Yao San was weakened by silencing.
The network pharmacology analysis revealed that mitogen-activated protein kinase 1 (MAPK1), MAPK3, serine/threonine-protein kinase (AKT1), proto-oncogene tyrosine-protein kinase (SRC), PI 3 kinase p85 alpha (PIK3R1), catenin (cadherin-associated protein) beta 1 (CTNNB1) and human thrombin activator 1 (HRAS) may be of importance to treat depression by Xiao Yao San.
Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that metabolic and autophagy pathways, pathways in cancer and MAPK, phosphoinositide 3-kinase (PI3K)-Akt and rhoptry-associated protein 1 (Rap1) signalling pathways are involved in the antidepressant effects of Xiao Yao San. As suggested by Western blot, the anti-depression mechanism of MXYS is possibly associated with the extracellular signal-regulated protein kinase (ERK)/P38 MAPK signaling pathway.
Conclusion: The findings indicate the possible antidepressant effects of Xiao Yao San on CUMS mice via triggering autophagy to alleviate neuronal apoptosis and prompting autophagy, which may involve the ERK/P38 MAPK signalling pathway.
Reference: https://pubmed.ncbi.nlm.nih.gov/38232859/