The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

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Abstract
Inflammatory bowel disease (IBD) is often triggered and/or exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs). Among various prostanoids affected by NSAIDs, prostaglandin E2 (PGE2), in particular, seems to play critical roles in IBD via the EP4 receptor, one of the four PGE2 receptor subtypes (EP1–4). An EP4 agonist, [[3-[[(1R,2S,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl]-5-oxocyclopentyl]thio]propyl]thio]-acetic acid, C22H30O6S2 (ONO-AE1–329), for example, when topically applied, has been reported to ameliorate typical colitis symptoms by suppressing the production of cytotoxic cytokines in the dextran sodium sulfate (DSS)-induced colitis model. EP4 agonists are also known, however, for their ability to protect epithelial cells from apoptosis in vitro, which may contribute to the protection of mucosal barrier functions. To investigate this potential application, we have tested another EP4-selective agonist in the DSS-indomethacin mouse colitis model. 7-[2-(3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester, C23H33NO4 (AGN205203), an analog from the 8-azapiperidinone series of EP4 agonists, is metabolically and chemically more stable than the ONO agonist, because of its lack of oxidizable sulfur atoms in the α-chain and of 11-OH group, a potential source of β-elimination reaction. Treatment of mice subcutaneously with AGN205203 at 3 mg/kg/day minimized colitis symptoms, such as weight loss, diarrhea, and colonic bleeding. Further histological examination of colons revealed healthy surface columnar epithelial cells free of erosion and ulceration compared with those without the drug treatment. At cellular level, the drug treatment decreased colon epithelial apoptosis, prevented goblet cell depletion, and promoted epithelial regeneration. AGN205203 may be unique among known EP4 agonists for its metabolic and chemical stability, and it is amenable to systemic applications for the prevention and recovery of IBD.