Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2011-06, Vol.300 (6), p.G929-G938
• Main Authors: Chumanevich, Alexander A, Causey, Corey P, Knuckley, Bryan A, Jones, Justin E, Poudyal, Deepak, Chumanevich, Alena P, Davis, Tia, Matesic, Lydia E, Thompson, Paul R, Hofseth, Lorne J
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - toxicity; Apoptosis; Apoptosis - drug effects; Arginine - metabolism; Citrulline - metabolism; Colitis - chemically induced; Colitis - enzymology; Colitis - pathology; Colitis - prevention & control; Colon - drug effects; Colon - enzymology; Colon - pathology; Crohn's disease; Cytokines; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Gastrointestinal Agents - administration & dosage; Gastrointestinal Agents - pharmacology; Gastrointestinal Agents - toxicity; HT29 Cells; Humans; Hydrolases - antagonists & inhibitors; Hydrolases - metabolism; Inflammation/Immunity/Mediators; Inflammatory bowel disease; Mice; Mice, Inbred C57BL; Ornithine - administration & dosage; Ornithine - analogs & derivatives; Ornithine - pharmacology; Ornithine - toxicity; Protein Processing, Post-Translational - drug effects; Protein-Arginine Deiminases; Risk assessment; Rodents; Side effects; Up-Regulation
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00435.2010

Inflammatory bowel diseases (IBDs), mainly Crohn's disease and ulcerative colitis, are dynamic, chronic inflammatory conditions that are associated with an increased colon cancer risk. Inflammatory cell apoptosis is a key mechanism for regulating IBD. Peptidylarginine deiminases (PADs) catalyze the posttranslational conversion of peptidylarginine to peptidylcitrulline in a calcium-dependent, irreversible reaction and mediate the effects of proinflammatory cytokines. Because PAD levels are elevated in mouse and human colitis, we hypothesized that a novel small-molecule inhibitor of the PADs, i.e., chloramidine (Cl-amidine), could suppress colitis in a dextran sulfate sodium mouse model. Results are consistent with this hypothesis, as demonstrated by the finding that Cl-amidine treatment, both prophylactic and after the onset of disease, reduced the clinical signs and symptoms of colitis, without any indication of toxic side effects. Interestingly, Cl-amidine drives apoptosis of inflammatory cells in vitro and in vivo, providing a mechanism by which Cl-amidine suppresses colitis. In total, these data help validate the PADs as therapeutic targets for the treatment of IBD and further suggest Cl-amidine as a candidate therapy for this disease.