Based on network pharmacology-molecular docking and experimental exploration, the preventive and therapeutic effects of dapagliflozin on gouty arthritis in rats were investigated

Objective Exploring the preventive and therapeutic effects of dapagliflozin (DAPA) on gouty arthritis (GA) in rats, and revealing its potential mechanism of action. Methods Potential targets of DAPA were identified from DrugBank, Swiss Target Prediction, CTD, and PharmMapper databases. Targets associated with gouty arthritis (GA) were retrieved from Gene Cards, DisGeNET, and NCBI databases. By taking the intersection of these two sets, common targets of DAPA and GA were determined. These common targets were then subjected to Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Use the CB-DOCK2 online molecular docking platform to dock DAPA with the core target and perform visual analysis. Thirty-two SPF-grade male SD rats were randomly divided into four groups, with eight rats in each: a blank control group, a model group, a 20 mg/kg DAPA group, and a 40 mg/kg DAPA group. Rats received daily gavage administration of the corresponding medication for eight consecutive days. On the fifth day, monosodium urate (MSU) crystal suspension was injected into the left ankle joint to establish an acute GA model. Samples were collected one hour after the final gavage. The swelling of the ankle joints was recorded at various time points. Hematoxylin and eosin (HE) staining was used to observe pathological changes in the synovial tissue of the ankle joints. Enzyme-linked immunosorbent assay (ELISA) was conducted to measure the levels of inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the peripheral blood of the rats. Western blotting was performed to detect the expression levels of signaling pathway proteins in the synovial tissue of the ankle joints. Results Based on network pharmacology analysis and molecular docking, it was found that targets were significantly enriched in the nucleotide binding oligomerization domain (NOD)-like receptor (NLR) signaling pathway, and the binding energies between the related core targets and DAPA were all <-7.0 kcal/mol. In animal experiments, regarding ankle joint swelling: compared with the model group, the 20 mg/kg DAPA group showed a significant reduction in ankle joint swelling at 72 hours post-modeling (p<0.05), and the 40 mg/kg DAPA group exhibited significant reductions in ankle joint swelling at both 48 and 72 hours post-modeling (p<0.01). For ankle joint HE staining: compared with the model group, DAPA-treated groups showed varying degrees of attenuation in pathological damage, including inflammatory cell infiltration, synovial tissue proliferation, and vascular proliferation in the ankle joints. Peripheral blood ELISA results: the levels of IL-1β and TNF-α in DAPA-treated groups were significantly lower than those in the model group (p<0.05). As for the protein expression levels of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) and cysteinyl aspartate-specific proteinase-1 (Caspase-1) in ankle joint synovium: compared with the model group, the expression of NLRP3 and Caspase-1 proteins was significantly reduced in DAPA-treated groups (p<0.05). Conclusion DAPA may alleviate the inflammatory response in acute GA in rats by inhibiting the NLRP3/Caspase-1 pathway.