Comparison of prostaglandin E2 receptor subtype 4 agonist and sulfasalazine in mouse colitis prevention and treatment.
Prodrugs of 5-aminosalicylic acid (5-ASA), such as sulfasalazine, have been the mainstay for the treatment and maintenance of inflammatory bowel disease (IBD) for decades, which is attributable to their antiadaptive immune activity. However, 5-ASA compromises regeneration of intestinal epithelia and induces apoptosis. The majority of patients eventually undergo colectomy. Agonists for the prostaglandin E(2) subtype 4 (EP4) receptor have been shown to protect epithelial barrier against colitis-inducing agents and could be valuable alternatives for sulfasalazine. Here, we compared sulfasalazine and a novel EP4 agonist for their abilities to prevent colitis induction and relieve symptoms of established colitis in a dextran sulfate sodium-indomethacin mouse model. The EP4 agonist dose-dependently alleviated weight loss in colitis mice. Compared with sulfasalazine at 100 mg/kg on the colitis induction model, the EP4 agonist at 0.2 mg/kg was superior in reducing colitis symptoms, preventing increase of innate immune cells, and ameliorating inflammation in colon. In mice with established colitis, sulfasalazine quickly reversed weight loss but with fading efficacy. The EP4 agonist, in contrast, had slow but sustained effects on body weight gain and was more efficacious in epithelial regeneration. Such temporal differences between sulfasalazine and the EP4 agonist actions seemingly led to no additive effect in combination therapy. In conclusion, the EP4 agonist would be more efficacious in the maintenance of remission because of both anti-innate immune responses and epithelial regeneration activity, whereas sulfasalazine would be more suitable for induction of remission because of its rapid onset of antiadaptive inflammation action.
Jiang
Guang-Liang
GL
Research and Development, Allergan Pharmaceuticals, Inc, 2525 Dupont Dr, Irvine, California 92612. jiang_guang-liang@allergan.com
Im
Wha Bin
WB
Donde
Yariv
Y
Wheeler
Larry A
LA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D003967:Diarrhea / Q000517:prevention & control; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004906:Erythrocyte Count; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists*; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006454:Hemoglobins; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012460:Sulfasalazine; D016264:Dextran Sulfate; D015232:Dinoprostone; D007213:Indomethacin