Silibinin's Effects against Methotrexate-Induced Hepatotoxicity in Adjuvant-Induced Arthritis Rat Model

Methotrexate (MTX) is the first drug of choice to treat several diseases, including rheumatoid arthritis. However, its administration is accompanied by severe side effects, most commonly hepatotoxicity. Hence, alternative therapies with a lower toxicity and fewer side effects are needed. This study aimed to investigate the antioxidant and hepatoprotective effects of silibinin (SIL, natural agent) against MTX-induced hepatotoxicity in an adjuvant-induced arthritis (AIA) rat model. Arthritic rats were treated with SIL (100 mg/kg) and/or methotrexate (2 mg/kg). Non-arthritic rats, arthritic untreated rats, and arthritic rats who received the vehicle were followed in parallel. SIL alleviated the systemic consequences of arthritis by restoring lost weight, decreasing the erythrocyte sedimentation rate, and ameliorating joint damage, which was evident both micro- and macroscopically. Additionally, SIL prevented the histopathological alterations in the liver and significantly reduced the liver damage caused by MTX and AIA, as shown by a decrease in the markers of liver damage (ALT and AST). Furthermore, SIL relieved the oxidative stress induced by AIA and MTX in liver tissue by decreasing the lipid peroxidation (MDA) levels and enhancing the antioxidant defense system (GSH levels; catalase and superoxide dismutase (SOD) activities). In conclusion, our results suggest that SIL is a potent antioxidant and hepatoprotective agent in arthritic rats. It markedly attenuated the progression and severity of the arthritic disease and eased the oxidative stress in liver tissue by improving the pro-oxidant/antioxidant balance.