Inflammation assumes a vital role in the pathogenesis of depression and in antidepressant treatment. Paeoniflorin (PF), a monoterpene glycoside analog possessing anti-inflammatory attributes, exhibits therapeutic efficacy on depression-like behavior in mice. The objective of this study was to evaluate the antidepressant effects of PF on depression elicited by the chronic unpredictable mild stress (CUMS) model and the precise neural sequence associated with the inflammatory process. In this study, we established an in vivo mouse model induced by CUMS and an in vitro BV2 cell model induced by LPS+ATP. The mechanism of PF for depression was assessed by the SIRT1 selective inhibitor EX-527. The findings demonstrated that PF significantly alleviated the damage of BV2 cells treated with LPS and ATP, inhibited the generation of ROS, up-regulated the expression of SIRT1 mRNA, and down-regulated the expression of nuclear NF-κB, p65, NLRP3, Caspase-1 and GSDMD-N in vitro. In vivo, PF mitigated the depressive-like behavior induced by CUMS, reduced the number of neurons, and decreased the secretion of pro-inflammatory factors IL-1β, IL-6, and TNF-α in the hippocampus. Immunohistochemical results indicated that PF attenuated CUMS-induced hyperactivation of microglia. Moreover, the expression level of SIRT1 in the hippocampus was augmented, while the protein levels of NF-κB, p65, NLRP3, Caspase-1, IL-1β and GSDMD-N were diminished after PF treatment. Additionally, the selective inhibition of SIRT1 attenuated the therapeutic effect of PF on depression. These results imply that PF possesses antidepressant properties that rely on SIRT1 signaling to regulate NLRP3 inflammasome inactivation.

Depression is one of the most common psychological disorders nowadays. Studies have shown that 20(S)-protopanaxatriol (PPT) can effectively improve depressive symptoms in mice. However, its mechanism needs to be further explored. In this study, we used an integrated approach combining network pharmacology and transcriptomics to explore the potential mechanisms of PPT for depression. First, the potential targets and pathways of PPT treatment of depression were screened through network pharmacology. Secondly, the BMKCloud platform was used to obtain brain tissue transcription data of chronic unpredictable mild stress (CUMS) model mice and screen PPT-altered differential expression genes (DEGs). Gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using network pharmacology and transcriptomics. Finally, the above results were verified by molecular docking, Western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR). In this study, we demonstrated that PPT improved depression-like behavior and brain histopathological changes in CUMS mice, downregulated nitric oxide (NO) and interleukin-6 (IL-6) levels, and elevated serum levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) after PPT treatment compared to the CUMS group. Eighty-seven potential targets and 350 DEGs were identified by network pharmacology and transcriptomics. Comprehensive analysis showed that transthyretin (TTR), klotho (KL), FOS, and the phosphatidylinositol 3-kinase–protein kinase B (PI3K-AKT) signaling pathway were closely associated with the therapeutic effects of PPT. Molecular docking results showed that PPT had a high affinity for PI3K, AKT, TTR, KL, and FOS targets. Gene and protein level results showed that PPT could increase the expression of PI3K, phosphorylation of PI3K (p-PI3K), AKT, phosphorylation of AKT (p-AKT), TTR, and KL and inhibit the expression level of FOS in the brain tissue of depressed mice. Our data suggest that PPT may achieve the treatment of depression by inhibiting the expression of FOS, enhancing the expression of TTR and KL, and modulating the PI3K-AKT signaling pathway.

Depression is one of the most common neurological diseases, which imposes a substantial social and economic burden on modern society. The purpose of this study was to explore the mechanism of total ginsenoside ginseng root (TGGR) in the treatment of depression through a comprehensive strategy combining network pharmacology, transcriptomics, and in vivo experimental validation. The Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database and literature were used to collect the main components and targets of TGGR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were applied to explore the underlying mechanisms. In addition, the chronic unpredictable mild stress (CUMS)-induced C57BL/6 mouse model was used to evaluate the antidepressant activity of TGGR. The results showed that TGGR improved depression-like behavior in mice and increased the decrease in serum 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) levels caused by CUMS. Combined network pharmacology and transcriptomic analysis showed that the AMP-activated kinase (AMPK) signaling pathway mainly enriched the core target. Immunohistochemistry, Western blotting, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to confirm whether TGGR exerts antidepressant effects by regulating this pathway. The results showed that TGGR has a regulatory impact on related proteins in the AMPK pathway, and the regulatory effect of TGGR on proteins was inhibited after the administration of related pathway inhibitors. In summary, total ginsenosides may regulate the AMPK signaling pathway and activate the sirtuin 1 (SIRT1) peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) pathway to have therapeutic effects on depression.