Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis

Current therapies for the treatment of rheumatoid arthritis (RA) do not work for all patients, can lose efficacy over time, and can have significant side eVects. The discovery of new, eVective therapies for RA remains an unmet medical need. The Amaryllidaceae isocarbostyril narciclasine was previously shown to prophylactically reduce paw swelling in rats with adjuvant-induced arthritis (AA). In this study, the efficacy of sodium narcistatin (SNS), a water-soluble cyclic phosphate pro-drug of narciclasine, was assessed in AA rats for anti-inflammatory and bone-sparing properties after disease onset. AA rats were given daily intraperitoneal injections of SNS (1.75, 3.5, or 5 mg/kg/day, in 500 ?l sterile endotoxin-free saline) or saline from disease onset through severe disease stages. Footpad widths and radiographic scoring were used as indicators of inflammation and joint destruction, respectively. Ex vivo cytokine production by peripheral blood mononuclear cells (PMBC), splenocytes, and draining lymph node (DLN) cells were determined using ELISAs. SNS treatment dose-dependently reduced joint inflammation (̃70%) and bone loss (̃50%) compared with AA controls. SNS treatment also reduced spleen weight (without aVecting body weight), pro-inflammatory cytokine production by PMBC, splenocytes, and DLN cells, and site-dependently altered Thelper (Th)1-/Th2-type and anti-inflammatory cytokine profiles. SNS dramatically reduces inflammation and has bone-sparing properties, possibly by reducing immune cell pro-inflammatory cytokine production. Our Wndings support the development of SNS as a therapeutic for RA.