YH12852, a potent and highly selective 5‐HT<sub>4</sub> receptor agonist, significantly improves both upper and lower gastrointestinal motility in a guinea pig model of postoperative ileus

Hussain, Zahid; Lee, Y. J.; Yang, Hyun; Jeong, Eun Jeong; Sim, Jae Young; Park, Hyo-Jin

doi:10.1111/nmo.13094

Cited by 6 publications

(5 citation statements)

References 40 publications

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“…The 5‐HT system mainly consists of 5‐HT, 5‐HT receptor and the serotonin selective reuptake transporter (SERT). Blocking 5‐HT3R and 5‐HT4R, the excitatory 5‐HT receptor will lead to decreased gastrointestinal motility, whereas using agonists promotes gastric emptying (Morita et al ., 2013 ; Hussain et al ., 2017 ). The 5‐HT pathway also includes tryptophan hydroxylase (TPH‐1) and Toll‐like receptors (TLR).…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture modulates the intestinal microecology to improve intestinal motility in spinal cord injury rats

Cheng

Liu

Wang

et al. 2021

Microbial Biotechnology

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Spinal cord injury (SCI) is a disease involving gastrointestinal disorders. The underlying mechanisms of the potential protective effects of electroacupuncture (EA) and 5-hydroxytryptamine (5-HT) system on SCI remain unknown. We investigated whether EA improves gut microbial dysbiosis in SCI and regulates the 5-HT system. 16S rDNA gene sequencing was applied to investigate alterations in the gut microbiome of the rats. Faecal metabolites and the expression of the 5-HT system were detected. EA and faecal microbiota transplantation (FMT) treatment facilitated intestinal transmission functional recovery and restored the colon morphology of SCI rats. The composition of the intestinal microbiota, including numbers of phylum Proteobacteria, class Clostridia, order Bacteroidales, and genus Dorea, were amplified in SCI rats, and EA and FMT significantly reshaped the intestinal microbiota. SCI resulted in disturbed metabolic conditions in rats, and the EA and FMT group showed increased amounts of catechin compared with SCI rats. SCI inhibited 5-HT system expression in the colon, which was significantly reversed by EA and FMT treatment. Therefore, EA may ameliorate SCI by modulating microbiota and metabolites and regulate the 5-HT system. Our study provides new insights into the pathogenesis and therapy of SCI from the perspective of microbiota and 5-HT regulation.

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Section: Introductionmentioning

confidence: 99%

Electroacupuncture modulates the intestinal microecology to improve intestinal motility in spinal cord injury rats

Cheng

Liu

Wang

et al. 2021

Microbial Biotechnology

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“…For example, bell shaped curve responses were reported in a study investigating the effects of a 5-HT4 agonist in a guinea pig model of postoperative ileus. 37 In conclusion, the concept that activation of luminal 5-HT 4 receptors could provide a safe and effective approach for the treatment of constipation is gaining momentum. 22 The findings described here reveal that novel, luminally acting 5-HT 4 R agonist compounds can generate prokinetic actions in the colon.…”

Section: Discussionmentioning

confidence: 99%

“…This was not the case for the dose–response relationship in the in vivo whole gut transit and fecal output studies reported here, but this was not necessarily unexpected based on previous studies of this receptor. For example, bell shaped curve responses were reported in a study investigating the effects of a 5‐HT4 agonist in a guinea pig model of postoperative ileus 37 …”

Section: Discussionmentioning

confidence: 99%

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Konen

Haag

Guseva

et al. 2020

Neurogastroenterology Motil

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Background: 5-HT 4 receptor (5-HT 4 R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT 4 Rs have limited their use. Since 5-HT 4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT 4 R agonists promote intestinal motility. Methods: Non-absorbed 5-HT 4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT 4 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-HT 4 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-HT 4 R antagonist and were not detected in 5-HT 4 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-HT 4 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-HT 4 Rs can potentiate propulsive motility and support the concept that mucosal 5-HT 4 Rs could represent a safe and effective therapeutic target for the treatment of constipation.

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“…Approximately 10% of 5-HT is produced in the ENS and central nervous system, which stimulates the local intestinal nerve reflex, triggers secretion and propulsion and acts on the motor Ma et al Journal of Translational Medicine (2023) 21:349 vagal afferent nerve to regulate contractile activity [85]. Using a POI model of guinea pigs, one study has shown that treatment with 5-HT4 agonists before surgery can significantly accelerate intestinal movement and improve POI [86]. At the same time, a meta-analysis found that treatment with 5-HT agonists can promote intestinal recovery post-surgery [87].…”

Section: Gut Microbiota Affect the Ens By Regulating 5-htmentioning

confidence: 99%

Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms

et al. 2023

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Gut microbiota is closely related to human health and disease because, together with their metabolites, gut microbiota maintain normal intestinal peristalsis. The use of antibiotics or opioid anesthetics, or both, during surgical procedures can lead to dysbiosis and affect intestinal motility; however, the underlying mechanisms are not fully known. This review aims to discuss the effect of gut microbiota and their metabolites on postoperative intestinal motility, focusing on regulating the enteric nervous system, 5-hydroxytryptamine neurotransmitter, and aryl hydrocarbon receptor.

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YH12852, a potent and highly selective 5‐HT₄ receptor agonist, significantly improves both upper and lower gastrointestinal motility in a guinea pig model of postoperative ileus

Abstract: Oral administration of YH12852 significantly accelerates and restores delayed upper and lower GI transit in a guinea pig model of POI. This drug may serve as a useful candidate for the treatment of postoperative ileus.

Cited by 6 publications

References 40 publications

Electroacupuncture modulates the intestinal microecology to improve intestinal motility in spinal cord injury rats

Electroacupuncture modulates the intestinal microecology to improve intestinal motility in spinal cord injury rats

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms

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YH12852, a potent and highly selective 5‐HT4 receptor agonist, significantly improves both upper and lower gastrointestinal motility in a guinea pig model of postoperative ileus

Abstract: Oral administration of YH12852 significantly accelerates and restores delayed upper and lower GI transit in a guinea pig model of POI. This drug may serve as a useful candidate for the treatment of postoperative ileus.

Cited by 6 publications

References 40 publications

Electroacupuncture modulates the intestinal microecology to improve intestinal motility in spinal cord injury rats

Electroacupuncture modulates the intestinal microecology to improve intestinal motility in spinal cord injury rats

Prokinetic actions of luminally acting 5‐HT4 receptor agonists

Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms

Contact Info

Product

Resources

About

YH12852, a potent and highly selective 5‐HT₄ receptor agonist, significantly improves both upper and lower gastrointestinal motility in a guinea pig model of postoperative ileus

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists