Date of Award

2020

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmacology

First Advisor

Gary Mawe

Abstract

The 5-hydroxytryptamine receptor 4 (5-HT4 receptor) is highly expressed in the gastrointestinal system on colonic epithelial cells and has been identified as a potential therapeutic target in altered bowel function and pain. 5-HT4 receptors influence propulsive motility, decrease sensitivity and visceral pain, increase enteric neuron survival, increase mucus secretion and mediate epithelial cell proliferation. Previous work in the Mawe laboratory has demonstrated that intraluminal application of the 5-HT4 receptor agonist, tegaserod, exerts protective actions in animal models of colitis as well as accelerate recovery from active colitis. The first aim of this study was to test a newly developed luminally acting 5-HT4 receptor agonist in two murine models of experimental colitis.

The luminally acting agonist (5HT4-LA1; Takeda Pharmaceuticals, 10mg/kg) was administered by enema to mice after they had developed active colitis. The degree of colitis was evaluated in vivo by monitoring weight loss, stool consistency and fecal blood content, and post mortem with histological damage scoring. Fecal water content was also evaluated to ascertain whether the luminally restricted agonist would result in excess water secretion and thus more severe diarrhea. Intracolonic administration of 5HT4-LA1 significantly accelerated recovery from active colitis as compared to administration of vehicle and antagonist, indicated by lower disease activity. There was however, no significant difference in the histological damage scores between groups. There was no significant difference in fecal water content between the agonist treated group and the vehicle treated group, indicating that the agonist does not worsen the loose stool promoted by inflammation.

The second aim of this investigation was to assess the same luminally restricted agonist in a mouse model of constipation. Previous work in the Mawe laboratory has demonstrated that mice with experimental autoimmune encephalomyelitis (EAE), an experimental mouse model of multiple sclerosis, exhibit alterations in motility that are consistent with constipation, including slower whole gut transit and colonic motility and drying stool. Motility studies conducted by the Mawe lab with the luminally restricted compound in healthy mice indicated that it increased motility. We tested whether administration of the luminally acting 5-HT4 agonist would alleviate the constipation symptoms in EAE mice. The luminally acting agonist was orally administered to EAE induced mice after confirming altered motility with motility assays to evaluate whole gut transit, colonic motility and fecal water content. Oral administration of the luminally restricted agonist significantly accelerated whole gut transit and colonic motility, and significantly increased fecal water content as compared to administration of vehicle solution.

In conclusion, the luminally acting agonist has therapeutic applications in both experimental mouse models of colitis and constipation. Administration of the agonist attenuated and accelerated recovery from active colitis, as well as relieved symptoms of constipation. These results suggest that epithelial 5-HT4 receptors could serve as a safe and effective target for treating colitis and constipation.

Language

en

Number of Pages

64 p.

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