Quercetin modulates the anti-arthritic effects of indomethacin, possibly through COXs and TNF-α interaction pathways

Quercetin (QUR) is a flavonoid compound with potent anti-oxidant and anti-inflammatory properties, commonly found in various fruits and vegetables. This study aims to evaluate the synergistic anti-arthritic effects of QUR in combination with indomethacin (INDO) in formaldehyde and turpentine oil-induced arthritis models in mice and to explore the underlying molecular mechanisms using in vivo and in silico approaches. Arthritis was induced in 60 male Swiss albino mice, divided into 12 groups. The animals were treated with QUR (12.5, 25, and 50 mg/kg), INDO (10 mg/kg), or a combination of QUR-25 and INDO-10, all administered per orally. Paw licking and edema were recorded at various intervals. Molecular docking studies assessed the binding of QUR and INDO to cyclooxygenase-1 (COX-1), COX-2, and tumor necrosis factor-alpha (TNF-α), while SwissADME and Protox-3.0 were used for drug-likeness, pharmacokinetics, and toxicity predictions. QUR significantly reduced paw edema and licking behavior in both models. QUR-50 mg/kg showed the most substantial anti-arthritic effects, comparable to or surpassing INDO, especially in the late phase. The combination of QUR and INDO exhibited enhanced efficacy, with a superior reduction in inflammation compared to either treatment alone. In silico docking revealed stronger binding affinities of QUR (-8.5, -8.9, -8.7 kcal/mol) for COX-1, COX-2, and TNF-α compared to INDO. QUR also showed better pharmacokinetic properties with lower toxicity. QUR demonstrates significant anti-arthritic potential, both alone and in combination with INDO, through COX and TNF-α interaction pathways. Further studies are needed to explore its long-term therapeutic efficacy.