Salicylalazine: A novel therapeutic agent targeting TLR4/NLRP3/GSDMD-mediated pyroptosis in rheumatoid arthritis.

Background: Joint pain and functional impairment are hallmarks of arthritis, a painful inflammatory disease. Salicylalazine (SAZ), an anti-inflammatory compound, has demonstrated promise in modulating inflammation, thereby being selected in the current study to unveil its anti-arthritic potential.

Objectives: The aim behind this study was to assess the anti-arthritic properties of salicylalazine via evaluating its impact on paw volume, arthritic scores, oxidative stress indicators, and significant inflammatory mediators.

Methods: The arthritic potential of SAZ was estimated first through the formaldehyde (FA) model to screen the most effective dose of SAZ, followed by the Complete Freund's adjuvant (CFA) model. Over a 28-day period, we monitored parameters such as paw edema, arthritic index, body weight, flexion pain, mobility, and stance score. Oxidative stress markers (GSH, CAT, SOD, MDA), serological markers (CRP, RF, anti-CCP), and gene expression of key inflammatory mediators (TLR4, MyD88, NFκB, NLRP3, ASC, IL-1β, IL-18, caspase-1, GSDMD) were assessed.

Results: SAZ treatment led to a substantial decrease in paw volume in both arthritis models, with the most pronounced effects observed on day 10 for the formaldehyde model and day 28 for the CFA model (p < 0.001). Additionally, SAZ helped to restore the body's weight and considerably relieved the flexion pain, which led to improvements in both mobility and stance. Moreover, SAZ substantially raised the levels of antioxidant enzymes (GSH, CAT, SOD) and decreased MDA levels, suggesting a reduction in oxidative stress. Also with SAZ, there was a substantial (p < 0.001) decrease in the expression of pyroptotic mediators. Serological markers of inflammation, including CRP, RF, and anti-CCP levels, were also restored by SAZ administration.

Conclusion: In a nutshell, SAZ achieved significant anti-arthritic benefits, most likely via the modulation of the TLR4/NLRP3/GSDMD-mediated pyroptosis pathway, lowering oxidative stress, and improvement of clinical findings. Taking into consideration these findings, it seems that SAZ has the potential to be an effective treatment alternative for the management of arthritis.