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

Gastroenterology. 1999 Sep;117(3):557-66. doi: 10.1016/s0016-5085(99)70448-8.


Background & aims: Nitric oxide (NO)-releasing derivatives of cyclooxygenase inhibitors exhibit enhanced anti-inflammatory activity and greatly reduced gastrointestinal toxicity. We evaluated whether a similar derivatization of mesalamine (5-aminosalicylic acid) would improve its anti-inflammatory activity.

Methods: Effects of an NO-releasing derivative of mesalamine (NCX-456; NO-mesalamine) were compared with those of mesalamine itself and 2 other 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)-1beta and interferon (IFN)-gamma release in vitro (splenocytes and colon), and messenger RNA expression in the inflamed colon.

Results: NO-mesalamine was significantly more effective than mesalamine in reducing 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-1beta 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-releasing derivative of mesalamine has significantly enhanced anti-inflammatory activity, including improved efficacy in a rat model of colitis. The improved efficacy of this derivative is most likely caused by its enhanced ability to suppress leukocyte infiltration and possibly to scavenge peroxynitrite.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminosalicylic Acids / pharmacology*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Caspase 1 / physiology
  • Cell Adhesion / drug effects
  • Cells, Cultured
  • Chemotaxis, Leukocyte / drug effects*
  • Colitis / drug therapy*
  • Colitis / immunology
  • Colitis / metabolism
  • Colitis / pathology
  • Colon / immunology
  • Disease Models, Animal
  • Endothelium, Vascular / immunology*
  • Endothelium, Vascular / pathology
  • Interferon-gamma / biosynthesis
  • Interleukin-1 / biosynthesis
  • Leukocytes / drug effects
  • Leukocytes / immunology*
  • Male
  • Mesalamine / pharmacology*
  • Nitric Oxide / analysis
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase Type II
  • RNA, Messenger / analysis
  • Rats
  • Rats, Wistar
  • Spleen / immunology


  • Aminosalicylic Acids
  • Anti-Inflammatory Agents, Non-Steroidal
  • Interleukin-1
  • RNA, Messenger
  • Nitric Oxide
  • Mesalamine
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Caspase 1