CPI-1189 Protects against TNBS-induced Colitis in a Rodent Model

Abstract: Nitrone-related therapeutics (NRTs) represents a new class of molecules that may be effective in treating inflammatory conditions. The goal of this study was to examine the effect of CPI- 1189 in a rat model of inflammatory bowel disease (IBD). Colonic inflammation was induced by an enema of trinitrobenzene sulfonic acid (TNBS). Saline-enema treated rats served as controls. After 3 days colonic damage was assessed morphologically using a validated scoring system and through measurement of myeloperoxidase (MPO), an enzymatic marker of inflammation. We found that a dose- dependent protection from TNBS-induced colonic damage was observed in rats given 10-70 mg kg¯1 of CPI-1189 treated p.o. 1 hr. before the TNBS enema. Consistent with the 55% absolute oral bioavailability of CPI-1189, greater protection (77%) was seen when CPI-1189 (30 mg kg¯1) was administered intravenously 1 hr. before the TNBS enema. In a separate series of healing experiments where CPI-1189 was administer after the TNBS inflammatory response had peaked, CPI-1189 at a dose of 90 mg kg¯1 p.o. reduced the TNBS colitis. CPI-1189 prevents and heals TNBS-induced colonic damage in rats suggesting that CPI-1189 may be a novel agent for the treatment of IBD.