Abstract
IL-17A is a pro-inflammatory cytokine that significantly contributes to the pathogenesis of autoimmune diseases, including multiple sclerosis (MS). Previous studies have suggested that PARP-1 inhibitors can modulate IL-17A-mediated inflammation, prompting the investigation of Niraparib, an FDA-approved PARP-1 inhibitor, as a potential therapeutic agent for MS. In this study, we hypothesized that Niraparib could disrupt the interaction between IL-17A and its receptor, IL-17RA. To evaluate this, we employed a binary quantitative structure-activity relationship (QSAR) model against anti-inflammatory diseases, which indicated Niraparib's potential efficacy against MS. In silico analyses were conducted to identify key interaction sites and critical amino acid residues involved in the IL-17A/IL-17RA binding. Molecular docking simulations demonstrated Niraparib's capability to interfere with these interactions. It has demonstrated significant efficacy in inhibiting the interaction between the IL-17A ligand and its receptor via reporter assay. In vivo assessments were performed using a cuprizone-induced demyelination model. Immune profiling revealed modulation of various T cell subsets and B cells, while cytokine analysis indicated a shift in inflammatory responses. Histological evaluations confirmed reduced demyelination and enhanced remyelination in affected brain regions. These findings support Niraparib's potential as a therapeutic option for MS, warranting further exploration of its mechanisms and clinical relevance.