Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat

• Published in: Regulatory peptides Vol. 179; no. 1-3; pp. 71 - 76
• Main Authors: Hellström, P.M., Smithson, A., Stowell, G., Greene, S., Kenny, E., Damico, C., Leone-Bay, A., Baughman, R., Grant, M., Richardson, P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.11.2012
• Subjects: Administration, Inhalation; Administration, Intravenous; Animals; Consciousness; Drug Evaluation, Preclinical; Electrodes, Implanted; Gastrointestinal motility; Gastrointestinal Motility - drug effects; Glucagon; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor; IBS; Injections, Subcutaneous; Intestine, Small - drug effects; Intestine, Small - metabolism; Irritable bowel syndrome; Irritable Bowel Syndrome - metabolism; Male; Myoelectric Complex, Migrating - drug effects; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Pulmonary delivery; Rats; Rats, Sprague-Dawley; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - metabolism; Statistics, Nonparametric; Time Factors; Gastrointestinal motility; IBS; Glucagon; Irritable bowel syndrome; Pulmonary delivery
• ISSN: 0167-0115; 1873-1686; 1873-1686
• DOI: 10.1016/j.regpep.2012.08.009

ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. Rats were implanted with bipolar electrodes at 5, 15 and 25cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100μg/kg) with or without the GLP-1 receptor blocker exendin(9–39)amide (300μg/kg·h), were studied. Second, ROSE-010 (100, 200μg/kg) Technosphere® powder was studied by inhalation. The baseline MMC cycle length was 17.5±0.8min. GLP-1 and ROSE-010, administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100μg/kg completely inhibited spiking activity for 49.1±4.2 and 73.3±7.7min, while the MMC cycle length increased to 131.1±11.4 and 149.3±15.5min, respectively. Effects of both drugs were inhibited by exendin(9–39)amide. Insufflation of ROSE-010 (100, 200μg/kg) powder formulation totally inhibited myoelectric spiking for 52.6±5.8 and 70.1±5.4min, and increased MMC cycle length to 102.6±18.3 and 105.9±9.5min, respectively. Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere® inhalation powder has potential in IBS pain management and treatment. ► The GLP-1 peptide analog ROSE-010 delivered by the pulmonary route with Technosphere® inhalation powder inhibits gut motility. ► Inhibition of gut motility by ROSE-010 works through the GLP-1 receptor similar to natural GLP-1. ► Technosphere® inhalation powder has the potential of pharmaceutical use of peptides like GLP-1 and ROSE-010.