exenatide and Constipation

BACKGROUND. There is increasing interest in methods to more rapidly and cost-efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration. METHODS. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinson's disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months). RESULTS. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037). CONCLUSION. These results demonstrate a potential cost-efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD.. Clinicaltrials.gov NCT01174810.. Cure Parkinson's Trust.

Topics: Aged; Antiparkinson Agents; Constipation; Disease Progression; Drug Repositioning; Exenatide; Female; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Male; Middle Aged; Motor Activity; Off-Label Use; Parkinson Disease; Peptides; Venoms; Weight Loss

Patients with irritable bowel syndrome (IBS) may experience postprandial symptom exacerbation. Nutrients stimulate intestinal release of glucagon-like peptide 1 (GLP-1), an incretin hormone with known gastrointestinal effects. However, prior to the postprandial rise in GLP-1, levels of the hunger hormone, ghrelin, peak. The aims of this study were to determine if ghrelin sensitizes colonic intrinsic and extrinsic neurons to the stimulatory actions of a GLP-1 receptor agonist, and if this differs in a rat model of IBS.. Calcium imaging of enteric neurons was compared between Sprague Dawley and Wistar Kyoto rats. Colonic contractile activity and vagal nerve recordings were also compared between strains.. Circulating GLP-1 concentrations differ between IBS subtypes. Mechanistically, we have provided evidence that calcium responses evoked by exendin-4, a GLP-1 receptor agonist, are potentiated by a ghrelin receptor (GHSR-1) agonist, in both submucosal and myenteric neurons. Although basal patterns of colonic contractility varied between Sprague Dawley and Wister Kyoto rats, the capacity of exendin-4 to alter smooth muscle function was modified by a GHSR-1 agonist in both strains. Gut-brain signaling via GLP-1-mediated activation of vagal afferents was also potentiated by the GHSR-1 agonist.. These findings support a temporal interaction between ghrelin and GLP-1, where the preprandial peak in ghrelin may temporarily sensitize colonic intrinsic and extrinsic neurons to the neurostimulatory actions of GLP-1. While the sensitizing effects of the GHSR-1 agonist were identified in both rat strains, in the rat model of IBS, underlying contractile activity was aberrant.

Topics: Animals; Colon; Constipation; Diarrhea; Electrophysiological Phenomena; Enteric Nervous System; Exenatide; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Irritable Bowel Syndrome; Muscle Contraction; Muscle, Smooth; Neurons; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Ghrelin; Vagus Nerve

Alterations in gut motility and visceral hypersensitivity are two major features of irritable bowel syndrome (IBS). The aim of this study was to investigate the roles of glucagon-like peptide-1 (GLP-1) in the pathogenesis of experimental IBS. Rat models of constipation-predominant IBS (IBS-C) and diarrhea-predominant IBS (IBS-D) were established. Fecal water content and behavioral responses to colorectal distention (CRD), using electromyography (EMG), were measured. The expression of glucagon-like peptide-1 receptor (GLP-1R) in the colon was detected by immunohistochemistry, and the serum concentration of GLP-1 was measured by ELISA assay. The movement of circular and longitudinal colonic muscle was detected using an organ bath recording technique. Compared to controls, the fecal water contents were lower in the IBS-C group, while they were higher in the IBS-D group (P<0.05). EMG response to CRD in the experimental IBS groups was increased compared with their respective controls (P<0.05). GLP-1R was localized in the mucosa layer, circular muscle and myenteric nerve plexus of the colon. Notably, the expression of GLP-1R in the IBS-C group was higher, but in the IBS-D group, it was lower compared with controls. The serum levels of GLP-1 in the IBS-C group were higher compared to those in the IBS-D group (P<0.05). In addition, administration of exogenous GLP-1 and exendin-4 inhibited colonic circular muscle contraction, particularly in the IBS-C group, while there was no significant effect on longitudinal muscle contraction. In conclusion, these results indicated that GLP-1 and GLP-1R are implicated in the pathogenesis of IBS-C and IBS-D.

Topics: Animals; Colon; Constipation; Diarrhea; Disease Models, Animal; Exenatide; Feces; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Irritable Bowel Syndrome; Male; Muscle Contraction; Peptides; Peristalsis; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms; Water