Evaluation of the effect of andrographolide and methotrexate combined therapy in complete Freund's adjuvant induced arthritis with reduced hepatotoxicity

Objective: Methotrexate is one of the most widely used disease-modifying anti-rheumatic drugs. The hepatotoxicity of methotrexate resulted in poor compliance with therapy. The current study was designed to analyse the combined therapy of andrographolide (AD) and methotrexate (MTX) for complete Freund's adjuvant (CFA)induced arthritis, focusing on hepatoprotective effects, oxidative stress and arthritic-related cytokines. Method: Wistar rats were injected with CFA into the right hind paw. Ten days post-CFA injection, the Wistar rats were administered with 1% CMC-Na solution, methotrexate (2 mg/kg/week), AD (50 mg/kg/d) and combined therapy for 35 days. The anti-arthritic effect was assessed by paw volume, X-ray and serum tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1 beta levels. Serum samples were also analysed for glutamic oxaloacetic transaminases (GOT), serum glutamic pyruvic transaminase (GPT), alkaline phosphatase (AKP) and lactate dehydrogenase (LDH). Liver tissue samples were used to examine the cellular antioxidant defence activities using catalase activity (CAT) and GSH as well as GSH-Px and MDA. Histopathology analysis was conducted to evaluate liver damage. Results: AD treatment strengthened the anti-arthritic capacity of MTX. AD and MTX-combined therapy additively reduced the inflammatory symptoms in CFA rats. The combined therapy of AD and MTX showed hepatoprotective effect indicated by an improvement in the serum marker, possibly due to antioxidant action and confirmed by liver histopathological changes. Furthermore, the combined therapy significantly reduced serum TNF-alpha, IL-6 and IL-1 beta levels. Conclusions: A combined therapy of AD and methotrexate significantly alleviated MTX-induced hepatocellular injury and strengthened the anti-arthritic effect. Further clinical studies should be done to further verify the possibility of combined its clinical usage.