Tumor necrosis factor-alpha, prostaglandin-E2 and interleukin-1 beta targeted anti-arthritic potential of fluvoxamine: drug repurposing

Fluvoxamine, a selective serotonin re uptake inhibitor, is used to treat depression. The aim of present study was to evaluate fluvoxamine in acute (egg albumin-induced inflammation) and chronic inflammatory rat models (formaldehyde and complete Freund's adjuvant (CFA)-induced arthritis). Fluvoxamine showed highly significant (p < 0.001) protective effect at dose of 50 mg/kg orally with percentage suppression 21.3% as compared to disease control group in acute model. Likewise, formaldehyde-induced arthritic experiment confirmed the significant (p < 0.001) anti-arthritic behavior, showed by fluvoxamine (50 mg/kg orally) throughout the study. Moreover, In CFA-induced model, the higher dose (fluvoxamine 50 mg/kg) exhibited highly significant (p < 0.001) decrease in paw thickness and arthritic score with significant increase in weight of animals from 123.8 +/- 1.934 g to 130.2 +/- 1.655 g, significantly decreased the level of RF and CRP to level of 12.0 +/- 0.707 and 11.40 +/- 0.50 respectively and restoration of SOD, CAT (69.8 +/- 1.5, 72.0 +/- 1.4 respectively). Furthermore, the level of TNF-alpha, PGE2, and IL-1 beta (147.0 +/- 2.0, 406.8 +/- 2.5, and 93.8 +/- 1.3 respectively) in arthritic animals was reduced to significant (p < 0.001) level (53.8 +/- 1.3, 205 +/- 3.6, and 42.0 +/- 1.4 respectively) after treatment with fluvoxamine. Furthermore, molecular docking of fluvoxamine against TNF-alpha, PGE2, and IL-1 beta protein targets showed good binding energies which hereby from computational studies proves our compound anti-inflammatory potential. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies reveled that fluvoxamine has very good pharmacokinetic profile with no specific hepatic toxicity and good absorption level. In addition, the skin sensitization test in vitro human cell line activation test (h-CLAT) and KeratinoSens have revealed that isolated flavone is not skin sensitive with confidence score of 59.6% and 91.6%. The current findings validated the anti-arthritic potential of fluvoxamine but it should be recommended for clinical investigation in future research.