The ghrelin agonist, HM01 activates central vagal and enteric cholinergic neurons and reverses gastric inflammatory and ileus responses in rats

• Published in: Neurogastroenterology and motility 2023-05, Vol.35 (5), p.e14561-n/a
• Main Authors: Yuan, Pu‐Qing, Wu, S. Vincent, Wang, Lixin, Taché, Yvette
• Format: Article
• Language: English
• Subjects: abdominal surgery; Agonists; Anesthesia; Animals; Blood-brain barrier; Cholinergic Neurons; Cytokines; dorsal motor nucleus of the vagus; Enteric nervous system; gastric cytokines; gastric ileus; Ghrelin; Ghrelin - metabolism; ghrelin receptor 1a; Ileus - metabolism; Inflammation; Inflammation - metabolism; Medulla oblongata; Motor nuclei; myenteric neurons; Myenteric plexus; Rats; Receptors, Ghrelin - metabolism; Vagus nerve; Vagus Nerve - physiology
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.14561

Background Electrical vagal stimulation alleviates abdominal surgery (AS)‐induced intestinal inflammation. Ghrelin receptors (GHS‐Rs) are expressed in the brain and peripheral tissues. We investigated the influence of HM01, an orally active ghrelin agonist crossing the blood–brain barrier, on AS‐induced gastric inflammation and emptying (GE) in rats. Methods HM01 (6 mg/kg) or saline pretreatment was administered per orally (po) or intraperitoneally (ip). We assessed GE, gastric cytokine mRNA, and Fos positive cells in the dorsal motor nucleus of the vagus (DMN) and gastric corpus myenteric plexus (MP) in sham (anesthesia alone) and AS groups. The transcripts of GHS‐R1 variants were determined in the medulla oblongata and gastric corpus of naïve rats. Key results In vehicle pretreated rats, HM01 (ip) significantly increased the number of Fos immunoreactive cells in the MP and DMN in 55% and 52% of cholinergic neurons respectively. Hexamethonium did not modify HM01‐induced Fos expression in the DMN while reducing it in the MP by 2‐fold with values still significantly higher than that in control groups. AS upregulated gastric IL‐1β and TNFα expression and inhibited GE by 66.6%. HM01 (po) abolished AS‐induced gastric ileus and increased cytokine expression and elevated IL‐10 by 4.0‐fold versus vehicle/sham. GHS‐R1a mRNA level was 5.4‐fold higher than the truncated GHS‐R1b isoform in the brain medulla and 40‐fold higher in the gastric submucosa/muscle layers than in the mucosa. Conclusions and inference Peripheral HM0 activates central vagal and myenteric cholinergic pathways that may influence both central and peripheral targets to prevent AS‐induced gastric inflammatory and ileus. Oral administration (PO) of ghrelin receptor agonist, HM01 prevented abdominal surgery (AS)‐delayed gastric emptying and inhibited AS‐induced increase of proinflammatory cytokines IL‐1β and TNFα, and upregulated IL‐10 in the rat gastric corpus submucosa plus muscle layers.