Ghrelin acts in the brain to block colonic hyperpermeability in response to lipopolysaccharide through the vagus nerve
Ghrelin acts in the brain to block colonic hyperpermeability in response to lipopolysaccharide through the vagus nerve
复制标题
生长素释放肽在大脑中发挥作用，通过迷走神经阻断结肠通透性过高，以响应脂多糖的作用
DOI：
10.1016/j.neuropharm.2020.108116
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发表时间：
2020
影响因子：
4.7
通讯作者：
Okumura Toshikatsu
中科院分区：
文献类型：
--
作者：
Ishioh Masatomo;Nozu Tsukasa;Igarashi Sho;Tanabe Hiroki;Kumei Shima;Ohhira Masumi;Okumura Toshikatsu
大脑Ghrelin在胃肠道功能中发挥作用。其中，Ghrelin起中枢作用，刺激胃肠运动，诱导内脏抗伤害性感觉。肠屏障功能是重要的胃肠功能之一，也受中枢神经系统的调控。然而，对中枢Ghrelin在调节肠道通透性中的作用知之甚少。本研究旨在阐明脑Ghrelin是否也参与肠道屏障功能的调节及其机制。通过定量大鼠结肠组织中吸收的伊文思蓝来评估体内的结肠通透性。脑池内注射Ghrelin可剂量依赖性地阻断对内毒素所致的结肠通透性增加，而相同剂量的Ghrelin或脑池内注射Des-acyl-Ghrelin均不能阻断该作用。卡巴胆碱可有效减轻内毒素诱导的肠道高通透性，阿托品或双侧膈下迷走神经切断术可预防中枢Ghrelin对肠道高通透性的改善。脑池内(D-Lys3)-GHRP-6是一种选择性的Ghrelin受体拮抗剂，可显著阻断静脉注射迷走神经中枢兴奋剂2-脱氧-d-葡萄糖对肠屏障功能的改善。脑池内注射食欲素1受体拮抗剂SB-334867可阻断Ghrelin诱导的结肠高通透性改善。这些结果表明，外源性给药或内源性释放的Ghrelin通过食欲素能信号和迷走神经胆碱能途径发挥中枢作用，改善受损的肠道屏障功能。中枢Ghrelin可能参与了胃肠道疾病的病理生理过程，不仅可用于肠易激综合征等胃肠道疾病的治疗，也可用于与肠道通透性改变相关的非胃肠道疾病的治疗。
Brain ghrelin plays a role in gastrointestinal functions. Among them, ghrelin acts centrally to stimulate gastrointestinal motility and induce visceral antinociception. Intestinal barrier function, one of important gastrointestinal functions, is also controlled by the central nervous system. Little is, however, known about a role of central ghrelin in regulation of intestinal permeability. The present study was performed to clarify whether brain ghrelin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of ghrelin dose-dependently abolished increased colonic permeability in response to LPS while intraperitoneal injection of ghrelin at the same dose or intracisternal injection of des-acyl-ghrelin failed to block it. Carbachol potently attenuated LPS-induced intestinal hyperpermeability, and atropine or bilateral subdiaphragmatic vagotomy prevented the improvement of intestinal hyperpermeability by central ghrelin. Intracisternal (D-Lys3)-GHRP-6, a selective ghrelin receptor antagonist, significantly blocked improvement of intestinal barrier function by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Intracisternal injection of orexin 1 receptor antagonist, SB-334867 blocked intracisternal ghrelin-induced improvement of colonic hyperpermeability. These results suggest that exogenously administered or endogenously released ghrelin acts centrally to improve a disturbed intestinal barrier function through orexinergic signaling and the vagal cholinergic pathway. Central ghrelin may be involved in the pathophysiology and be a novel therapeutic option in not only gastrointestinal diseases such as irritable bowel syndrome but also non-gastrointestinal diseases associated with the altered intestinal permeability.