Comparative Study of the Effect of Allopurinol and Nabumetone either Alone or Combined on Freund’s Adjuvant-Induced Arthritis in Rats

Background: Non steroidal anti-inflammatory drugs (NSAIDs) partially alleviate symptomatic manifestation of rheumatoid arthritis (RA) but do not provide long term protection from articular damage. Nabumetone possesses a powerful anti-inflammatory profile as convential NSAIDs, with little gastric and renal side effects due to selective blocking of Cyclooxygenase-2 (COX-2), thus prevent formation of prostaglandins (PGs) responsible for the cardinal signs of inflammation. Over expression of XO enzyme, overproduction of free radicals plus release of inflammatory cytokines has been shown to be involved in the inflammation-induced tissue damage. Xanthine oxidase (XO) inhibitors as allopurinol may retard disease progression most probably due to an antioxidant effect. Hence, XO inhibitors/NSAIDs combinations may help to achieve both long term prevention of disease progression as well as rapid onset of symptomatic control. Aim of the Work: This study was designed to compare the biochemical and pharmacological effects of allopurinol, nabumetone and their combination in RA. Material and Methods: Forty male rats were used, divided into five groups (8 rats each): Control group, Complete Freund's Adjuvant (CFA) induced RA group-not treated-, arthritic group treated with allopurinol, arthritic group treated with nabumetone and arthritic group treated with allopurinol plus nabumetone. After 6 weeks of treatment, the anti-inflammatory and antioxidant effects of the tested drugs on the severity of arthritis was evaluated by ELISA assay of serum TNF-α , a critical inflammatory mediator in this condition, calorimetric assay of serum uric acid due the evidence of increased XO activity in serum and tissue in patients with RA and by calorimetric assay of the oxidative stress parameters, lipid peroxides (LPO) and superoxide dismutase (SOD), due to overproduction of reactive oxygen species (ROS) during inflammatory process. Results: In the arthritic non-treated group, the serum levels of TNF-α , uric acid and LPO were significantly higher while the activity of SOD was significantly lower than the control group; also there was a significant difference in right hind paws thickness between the two groups. In the allopurinol Correspondence to: Dr. Soha S. Essawy, E-mail: [email protected]. treated group, the activity of SOD was significantly increased while the serum levels of TNFα , LPO, uric acid and right hind paws thickness were significantly decreased in comparison with the arthritic non-treated group. Nabumetone induced a significant decrease in the levels of TNFα and LPO and a significant increase in SOD activity accompanied by a significant decrease in right hind paws thickness in comparison with the arthritic non-treated group. Combination of allopurinol and nabumetone induced also a significant improvement of all serum bio-indices and right hind paws thickness compared to other treated group, this improvement was still significantly different from the non-arthritic control group. Conclusion: Both allopurinol and nabumetone showed anti-inflammatory and antioxidant effects in CFA-induced arthritis in rats. Addition of allopurinol to nabumetone induced a synergistic effect evidenced by reducing paw edema, free radical generation and improves antioxidant status.