Enhanced anti-inflammatory effects of a nitric oxide-releasing derivative of mesalamine in rats

Background & Aims: Nitric oxide (NO)-releasing derivatives of cyclooxygenas e inhibitors exhibit enhanced anti-inflammatory activity and greatly reduce d gastrointestinal toxicity. We evaluated whether a similar derivatization of mesalamine (5-aminosalicylic acid) would improve its anti-inflammatory a ctivity, Methods: Effects of an NO-releasing derivative of mesalamine (NCX- 456; NO-mesalamine) were compared with those of mesalamine itself and 2 oth er NO donors in a rat model of colitis. These drugs were compared for their ability to inhibit leukocyte adherence to the vascular endothelium in vivo , interleukin (IL)-1 beta and interferon (IFN)-gamma release in vitro (sple nocytes and colon), and messenger RNA expression in the inflamed colon. Res ults: NO-mesalamine was significantly more effective than mesalamine in red ucing the severity of colitis (damage and granulocyte infiltration). Unlike mesalamine, NO-mesalamine significantly suppressed leukocyte adherence to the vascular endothelium in vivo. NO-mesalamine inhibited IL-1 beta and IFN -gamma release and caspase 1 activity in splenocytes; such effects were not found in the inflamed colon. Conclusions: These studies show that an NO-re leasing derivative of mesalamine has significantly enhanced anti-inflammato ry activity, including improved efficacy in a rat model of colitis. The imp roved efficacy of this derivative is most likely caused by its enhanced abi lity to suppress leukocyte infiltration and possibly to scavenge peroxynitr ite.