The Anti-Arthritic Role of Naringenin through Modulating Different T Helper Cells’ Cytokines, Inflammatory Mediators, Oxidative Stress and Anti-Oxidant Defense System

Background: Rheumatoid arthritis (RA) is a systemic inflammatory disorder that is usually treated with a cocktail of steroidal and nonsteroidal anti-inflammatory drugs, as well as other therapeutic modalities known as disease-modifying anti-rheumatic drugs (DMARDs), all of which have significant side effects. Our objective was to investigate the potential impact of naringenin on a rat model of RA induced by Complete Freund’s Adjuvant (CFA). Methods: This was achieved by assessing T-helper (Th) cytokines, oxidative stress, and the anti-oxidant defense system. Eighteen Wistar rats were divided into three equal (n = 6) groups: the normal group, the CFA-induced arthritic control group, and the CFA-induced arthritic group treated with naringenin at a dose of 25 mg/kg body weight daily for two weeks. The study used a variety of techniques, including spectrophotometric analysis, enzyme-linked immunosorbent assay (ELISA), and Western blot procedures, as well as ankle histological investigations and measurement of ankle circumference of the right hind leg. Results: Naringenin treatment significantly decreased the CFA-induced elevated right hind-ankle circumference, serum rheumatoid factor (RF), anti-cyclic citrullinated peptide (ACCP), prostaglandin E₂ (PGE₂), tumor necrosis factor-α (TNF-α), and serum interleukin (IL)-1β levels (p < 0.05). Naringenin significantly increased serum IL-4 levels, hepatic glutathione (GSH), and superoxide dismutase (SOD) activity when compared to the CFA-induced RA model (p < 0.05). Naringenin treatment decreased ankle joint protein expression of nuclear factor kappa B (NF-κB) p50, NF-κB p65, inhibitor of NF-κB (IκBα), matrix metalloproteinases (MMPs)-1, 3 and 9, and inducible nitric oxide synthase (iNOS), as well as malondialdehyde (MDA) and nitric oxide (NO) levels (p < 0.05). Additionally, there was a significant increase in the ankle’s nuclear factor erythroid 2-related factor 2 (Nrf2) levels (p < 0.05). Morphological signs like leg swelling and redness were also significantly reduced. Naringenin treatment significantly improved RA’s histological changes, such as pannus formation, massive inflammatory cell infiltration, synovial membrane hyperplasia, and articular cartilage erosion. Conclusions: Naringenin has a potent anti-arthritic effect via modulating Th cells cytokines, NF-κB pathway, Nrf2, MMPs, free radical damage, and anti-oxidant defenses.