Amitriptyline Ameliorates Arthritis by Downregulation of Inflammatory Mediators and Oxidative Stress; A Mechanistic Approach

Abstract This study was designed to evaluate the antioxidant and anti-arthritic potential of amitriptyline. The albumin and formaldehyde were used to induce acute and chronic inflammation respectively. The adjuvant-induced arthritis model was developed in rats. In acute model, amitriptyline significantly (p < 0.001) decreased the thickness of paw at early as well as late stages. At high dose of test drug, the significant (p < 0.001) anti-arthritic effect was noted in formaldehyde-induced arthritic model. Likewise, Amitriptyline (40 mg/kg oral dose) produced a 4.7% decrease in swelling of paw prompted by CFA on day 14 that increased to17.09% on day 28. This effect significantly increased by higher dose of Amitriptyline 80 mg/kg (28.63%) on day 28th. The significant (p < 0.001) expression of antioxidant enzyme SOD (super oxide dismutase) was observed at maximum dose (80 mg/kg). Amitriptyline significantly reduced the levels of inflammatory cytokines like prostaglandin E2, TNF-α and NF-kB and the results were comparable with naproxen. Further, in-depth molecular docking and simulations studies of amitriptyline showed that it has good binding capacity with inflammatory cytokines showing the highest score with prostaglandin E2. In addition, ADMET studies also proved amitriptyline within the limits of Lipinski’s rule of five. These findings validate the anti-arthritic effect of amitriptyline, but it has limitations for clinical studies.