Inhibition of the nucleoside transporter inhibits disease progression in the rat adjuvant-induced arthritis model

We investigated the in vivo effects of the nucleoside transporter inhibitor nitrobenzylmercaptopurine (NBMPR) on rat adjuvant-induced arthritis. This agent inhibits uptake of adenosine into cells, presumably leading to increased levels of extracellular adenosine. Arthritis was induced in 7-week-old male Lewis rats by injection of incomplete Freund's adjuvant containing heat-killed Mycobacterium butyricum into the base of the tail on day 0. The rats were then treated from day 0 with daily intraperitoneal injections of NBMPR (50 mg/kg/d in 1 ml of saline) or saline alone (untreated). The onset and progression of arthritis was evaluated daily using the arthritis severity index (0-4) for swelling and redness in four joints (bilateral front- and hind-paws), with a score of 0 representing no rheumatoid changes and a score of 4 representing the most severe changes. Body weights were also measured to monitor the systemic antiarthritic effects of NBMPR as well as its systemic toxicity. On the last day (day 35), the rats were killed, and radiographic and histopathological assessments of their hind-paws were conducted. The onset of arthritis was detected on the same day in both NBMPR-treated and untreated arthritic rats, but subsequent disease progression was suppressed significantly in NBMPR-treated rats. Radiographic (e.g., bone erosion and destruction) and histopathological (e.g., cell infiltration and cartilage erosion) findings confirmed the improved condition of the NBMPR-treated rats. There was no significant difference in body weight among the rats. Thus, increasing extracellular adenosine with NBMPR appears to suppress the progression of arthritis. (C) 2003 Wiley-Liss, Inc.