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

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 117; no. 3; pp. 557 - 566
• Main Authors: Wallace, John L., Vergnolle, Nathalie, Muscará, Marcelo N., Asfaha, Samuel, Chapman, Kevin, McKnight, Webb, Soldato, Piero Del, Morelli, Antonio, Fiorucci, Stefano
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-09-1999; Elsevier
• Subjects: Aminosalicylic Acids - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; 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; Medical sciences; Mesalamine - pharmacology; Nitric Oxide - analysis; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase Type II; Pharmacology. Drug treatments; Rats; Rats, Wistar; RNA, Messenger - analysis; Spleen - immunology; NO; DTT; IBD; FMLP; IL-1β; TNBS; MPO; LPS; IFN-γ; Ac-YVAD-CHO; RT-PCR; AMC; iNOS; GAPDH; AFC; HPLC; ELISA; Rat; Treatment efficiency; Rodentia; Cytokine; Inflammatory disease; Non steroidal antiinflammatory agent; Crohn disease; Vertebrata; Experimental disease; Mammalia; Mesalazine; Animal; Nitric oxide; Digestive diseases; Intestinal disease; Salicylates; Derived product; Release; Ulcerative colitis
• ISSN: 0016-5085; 1528-0012
• 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)-1β and interferon (IFN)-γ 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-1β and IFN-γ 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.
GASTROENTEROLOGY 1999;117:557-566