TY - JOUR T1 - A Comparison of the Central Versus Peripheral Gastrointestinal Prokinetic Activity of Two Novel Ghrelin Mimetics. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.250738 SP - jpet.118.250738 AU - Ehsan Mohammadi AU - Claudio Pietra AU - Claudio Giuliano AU - Li Fugang AU - Beverley Greenwood-Van Meerveld Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/10/30/jpet.118.250738.abstract N2 - Background: The gastrointestinal (GI) prokinetc effects of ghrelin occurs through direct peripheral effects on ghrelin receptors within the enteric nervous system (ENS) and via ghrelin receptor on the vagus nerve which activate a centrally mediated mechanism. However, the relative contribution of peripheral versus central effects contributing to the overall prokinetic effect of ghrelin agonists requires further investigation. Here we investigated the central versus peripheral prokinetic effect of ghrelin by employing two novel ghrelin agonists, HM01 acting centrally and HM02, a peripherally restricted ghrelin agonist. Methods: The PK profile of both ghrelin agonists was evaluated after intravenous administration (i.v.) and oral (p.o.) administration in rat. The efficacy of HM01 and HM02 was assessed in a rat model of post-operative ileus (POI) induced by abdominal surgery and in a rodent defecation assay. Results: PK results confirmed in our models that HM01 but not HM02 was a brain penetrant ghrelin agonist. Administration of either HM01 or HM02 reversed the delay upper and lower gastrointestinal transit induced by abdominal surgery to levels resembling the non-POI controls. In the defecation test, HM01 but not HM02 significantly increased the weight of fecal pellets. Conclusion: Our findings suggest that in a rodent model of POI, synthetic ghrelin agonists stimulate GI transit though a peripheral site of action. However, in the defecation assay our data suggests that a ghrelin-mediated mechanism is located at a central site. Taken together, a ghrelin agonist with both central and peripheral prokinetic activity may show therapeutic potential to treat delayed GI transit disorders. ER -