Comparison of Prostaglandin E₂ Receptor Subtype 4 Agonist and Sulfasalazine in Mouse Colitis Prevention and Treatment

Abstract

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 dosedependently 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.

Prevention of Trinitrobenzene Sulfonic Acid-Induced Experimental Colitis by Oral Administration of a Poly(lactic-coglycolic Acid) Microsphere Containing Prostaglandin E2 Receptor Subtype 4 Agonist

“…Previous studies with EP4 agonists in a mouse IBD model of 3/5% dextran sodium sulfate-induced colitis revealed their ability to inhibit the innate immune response (Kabashima et al, 2002;Nitta et al, 2002), their antiapoptotic activity on intestinal epithelial cells, and a stimulating effect on mucous secretion from Goblet cells (Jiang et al, 2007(Jiang et al, , 2010. In the present TMBS-induced mice colitis model, it was found that pretreatment by the EP4 agonist significantly reduced colonic inflammation reactions and facilitated a recovery in body weight.…”

“…EP4-selective agonists therefore represent a novel class of immune-modulator drugs that could be useful for the management of inflammatory diseases such as arthritis (Shibata-Nozaki et al, 2011), sepsis (Sakamoto et al, 2004), inflammatory pain (Omote et al, 2002), and colitis (Kabashima et al, 2002;Nitta et al, 2002;Jiang et al, 2007Jiang et al, , 2010. In a human study, patients with UC refractory to 5-ASA responded favorably to treatment with [[3-[[(1R) (Nakase et al, 2010).…”

“…Several studies showed that prostaglandin (PG) E 2 -PGE 2 receptor subtype 4 (EP4) signaling is an important regulator of mucosal immune response, and EP4 has emerged an alternative therapeutic target for IBDs (Kabashima et al, 2002;Nitta et al, 2002;Jiang et al, 2007Jiang et al, , 2010. EP4 knockout mice are most susceptible to experimental colitis induction by oral intake of 5% dextran sodium sulfate, which is one of the common reproducible murine colitis models of IBDs.…”

Integrative Approach to Analyze Biodiversity and Anti-Inflammatory Bioactivity of Wedelia Medicinal Plants

“…To assess the extent of colitis in test mice, body weight, stool consistency and fecal occult blood were monitored daily using a method modified from Cooper et al [ 32 ]. Hemoccult was assessed by the guaiac paper test (Hemoccult SENSA, Beckman Coulter) and scored as follows: 0, normal; 2, trace positive; 3, strong positive; 4, gross bleeding [ 33 – 35 ]. The definitions of the disease activity index (DAI) are outlined in S1 Table .…”

Suppression of acute rejection by administration of prostaglandin E2 receptor subtype 4 agonist in rat organ transplantation models

“…Moreover, studies involving murine colitis models of inflammatory bowel diseases 6 revealed that EP4 works to suppress innate immunity and facilitate the proliferation of regulatory T cells (7). Selective EP4 agonists have also been reported to inhibit the production of chemokines and cytotoxic cytokines from immune cells, which suppress helper T 1 cell differentiation, and promote epithelial cell survival and growth by activating anti-apoptotic and proliferative cellular signaling pathways (3,8,9).…”