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
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
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DOI：
10.1111/nmo.13094
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发表时间：
2017-10-01
影响因子：
3.5
通讯作者：
Park, H.
中科院分区：
文献类型：
--
作者：
Hussain, Z.;Lee, Y. J.;Park, H.
背景：术后肠梗阻(POI)是腹部手术后常见的一过性胃肠运动障碍。YH12852是一种新型、高效、高选择性的5-羟色胺4(5-HT4)受体激动剂，多种动物研究表明，它可以改善上、下消化道动力，并可能用于POI的治疗。本研究通过观察YH12852对豚鼠POI模型的影响及其作用机制，探讨YH12852对POI的治疗作用。方法：采用开腹、剔除盲肠，轻按盲肠60s，麻醉下缝合缝合的方法建立POI豚鼠模型。第1组仅口服Vehicle或YH12852(1、3、10或30 mg/kg)，而POI组2在口服Vehicle或YH12852(3或10 mg/kg)之前预先给予Vehicle或5-HT4受体拮抗剂GR113808(10 mg/kg)。结果：YH12852在3、10、30 mg/kg剂量下对上、下胃肠道转运均有明显促进作用，10 mg/kg时效果最好。GR113808 10 mg/kg可显著阻断上述作用。结论：口服YH12852可显著加快和恢复POI豚鼠模型的上、下胃肠道传递延迟。该药可作为治疗术后肠梗阻的有效候选药物。
Background: Postoperative ileus (POI) is a transient gastrointestinal (GI) dysmotility that commonly develops after abdominal surgery. YH12852, a novel, potent and highly selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist, has been shown to improve both upper and lower GI motility in various animal studies and may have applications for the treatment of POI. Here, we investigated the effects and mechanism of action of YH12852 in a guinea pig model of POI to explore its therapeutic potential.Methods: The guinea pig model of POI was created by laparotomy, evisceration, and gentle manipulation of the cecum for 60 seconds, followed by closure with sutures under anesthesia. Group 1 received an oral administration of vehicle or YH12852 (1, 3, 10 or 30 mg/kg) only, while POI Group 2 was intraperitoneally pretreated with vehicle or 5-HT4 receptor antagonist GR113808 (10 mg/kg) prior to oral dosing of vehicle or YH12852 (3 or 10 mg/kg). Upper GI transit was evaluated by assessing the migration of a charcoal mixture in the small intestine, while lower GI transit was assessed via measurement of fecal pellet output (FPO).Key Results: YH12852 significantly accelerated upper and lower GI transit at the doses of 3, 10, and 30 mg/kg and reached its maximal effect at 10 mg/kg. These effects were significantly blocked by pretreatment of GR113808 10 mg/kg.Conclusion and Inferences: 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.