Xiegan-Liangxue-Jiedu Decoction Alleviated Psoriasis and Depressionlike Behavior in a Mouse Model: Role of the AC–cAMP–PKA–CREB Signaling Pathway

Abstract

Objectives: Psoriasis vulgaris is an immune-mediated inflammatory skin disease that is associated with depression. In this study, we investigated the effect of Xiegan–Liangxue–Jiedu (XGLXJD) decoction, a traditional Chinese medicine formula, on psoriasis based on network pharmacology, molecular docking, and animal experiments.Materials and Methods: A protein–protein interaction (PPI) network was constructed using the overlapping targets of XGLXJD decoction and psoriasis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using Metascape database. High-performance liquid chromatography (HPLC) was used to investigate the main compounds of XGLXJD decoction. Molecular docking was performed to predict the potential interaction between the main compounds and proteins of interest. A C57 mouse model of psoriasis was established via continuous exposure to imiquimod. Seven days later, the XGLXJD decoction was orally administered at increasing doses for 6 days. The psoriasis area and severity index were calculated. Hematoxylin and eosin staining was used to examine skin morphology. Enzymelinked immunosorbent assay (ELISA) was used to determine the serum levels of adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α). Sucrose preference test and forced swimming test were used to assess depression-like behavior. Immunohistochemical (IHC) staining and immunofluorescence were used to investigate the cAMP-response element binding protein (CREB) signaling pathway.Results: Overall, 162 overlapping targets were generated. A total of 398 biological processes, 84 molecular functions, and 47 cellular components were identified via GO analysis, whereas 140 pathways were identified via KEGG pathway analysis. The most notable signaling pathways were cAMP as well as downstream IL-17 and TNF-α signaling pathways. HPLC analysis revealed that the main compounds of XGLXJD decoction were paeoniflorin, isorhamnetin, quercetin, luteolin, kaempferol, and baicalein. The molecular docking assay indicated that the docking energies of the main compounds of XGLXJD decoction to the top hub genes were less than −5 kcal/mol. ELISA revealed that the administration of XGLXJD decoction decreased the levels of pro-inflammatory cytokines (TNF-α and IL-17). Furthermore, the AC, cAMP, and PKA levels were enhanced after its administration. IHC staining demonstrated that the administration of XGLXJD decoction activated the AC–cAMP– PKA–CREB signaling pathway in skin. In addition, it enhanced sucrose preference and forced swimming time percentage. It also enhanced the expression of cAMP and PKA in the hippocampus.Conclusion: XGLXJD decoction alleviated psoriasis and depression-like behavior. The AC–cAMP–PKA–CREB signaling pathway may play a crucial role in mediating this effect.

Keywords: Network pharmacology; molecular docking; psoriasis; cAMP–PKA–CREB signaling pathway