Anti-arthritic and anti-inflammatory potential of newly synthesized 2,3-disubsituted thiazolidine-4-one derivatives in CFA-induced arthritis model by targeting TLR4/NF-κB and MAPK signaling.

backgroundRheumatoid arthritis (RA) is a long-term autoimmune disorder associated with severe inflammation and primarily causes joint destruction. The present study explored the anti-arthritic and anti-inflammatory potential of two newly synthesized 2,3-disubsituted thiazolidine-4-one derivatives in a Complete Freund’s Adjuvant (CFA)-induced arthritis in BALB/c mice by targeting TLR4/NF-κB and MAPK signaling pathway.

methodsAcute inflammatory arthritis was induced by administering CFA (1 mg/ml, 20 µL) via intraplantar route (i.pl.) into the right hind paw of BALB/c mice. Animals were treated intraperitoneally (i.p.) with (E)-3-benzyl-2-((Z)-(1-(4-bromophenyl)ethylidene)hydrazono)thiazolidin-4-one (BEHT) and (E)-2-((Z)-(1-(4-chlorophenyl)ethylidene)hydrazono)-3-(4-nitrobenzoyl)thiazolidin-4-one (CEHNT) (1, 5, or 10 mg/kg). The anti-arthritic potential of BEHT and CEHNT was evaluated through nociceptive tests, histopathology, antioxidant assays, and biomolecular parameters.

resultsBEHT and CEHNT markedly suppressed CFA-induced pain hypersensitivity and paw edema dose dependently. Histopathological investigation showed improvement by attenuating cellular infiltration, edema, and fibrosis following BEHT and CEHNT administration. Both compounds also decreased serum C-reactive protein (CRP) levels and restored antioxidant enzyme activities, while simultaneously reducing oxidative stress. Likewise, BEHT and CEHNT markedly downregulated toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2), p38, and extracellular signal-regulated kinase (ERK) while upregulating the inhibitor of nuclear factor kappa B (IκB-α) expression as well as suppressing the release of tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Molecular docking further demonstrated strong binding affinities of both compounds against TLR4, NF-κB, IκB-α, COX-2, p38, and pERK protein targets.

conclusionBEHT and CEHNT demonstrated promising anti-arthritic potential in the acute phase of CFA-induced arthritis via inhibition of oxido-inflammatory signaling by altering the TLR4, NF-κB, IκB-α, COX-2, p38, and pERK expression.