Protective actions of a luminally acting 5-HT4 receptor agonist in mouse models of colitis.

BACKGROUND: 5-hydroxytryptamine 4 receptors (5-HT4 Rs) are expressed in the colonic epithelium, and previous studies have demonstrated that luminal administration of agonists enhances motility, suppresses nociception, and is protective in models of inflammation. We investigated whether stimulation with a luminally acting 5-HT4 R agonist is comparable to previously tested absorbable compounds. METHODS: The dextran sodium sulfate (DSS), trinitrobenzene sulfonic acid (TNBS), and interleukin 10 knockout (IL-10KO) models of colitis were used to test the protective effects of the luminally acting 5-HT4 R agonist, 5HT4-LA1, in the absence and presence of a 5-HT4 R antagonist. The compounds were delivered by enema to mice either before (prevention) or after (recovery) the onset of active colitis. Outcome measure included disease activity index (DAI) and histological evaluation of colon tissue, and effects on wound healing and fecal water content were also assessed. KEY RESULTS: Daily enema of 5HT4-LA1 attenuated the development of, and accelerated recovery from, active colitis. Enema administration of 5HT4-LA1 did not attenuate the development of colitis in 5-HT4 R knockout mice. Stimulation of 5-HT4 Rs with 5HT4-LA1 increased Caco-2 cell migration (accelerated wound healing). Daily administration of 5HT4-LA1 did not increase fecal water content in active colitis. CONCLUSIONS AND INFERENCES: Luminally restricted 5-HT4 R agonists are comparable to absorbable compounds in attenuating and accelerating recovery from active colitis. Luminally acting 5-HT4 R agonists may be useful as an adjuvant to current inflammatory bowel disease (IBD) treatments to enhance epithelial healing.

Prokinetic actions of luminally acting 5-HT4 receptor agonists.

BACKGROUND: 5-HT4 receptor (5-HT4 R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT4 Rs have limited their use. Since 5-HT4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT4 R agonists promote intestinal motility. METHODS: Non-absorbed 5-HT4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT4 R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. KEY RESULTS: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT4 R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT4 R antagonist and were not detected in 5-HT4 R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT4 R is present in the epithelial layer of the human small and large intestines. CONCLUSIONS AND INFERENCES: These findings demonstrated that stimulation of epithelial 5-HT4 Rs can potentiate propulsive motility and support the concept that mucosal 5-HT4 Rs could represent a safe and effective therapeutic target for the treatment of constipation.