title: New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson's disease.
abstract: BACKGROUND
  Constipation and L-dopa-induced gastric dysmotility are common gastrointestinal (GI) symptoms in Parkinson's disease (PD). We investigated the novel ghrelin agonist, HM01 influence on GI motor dysfunctions in 6-hydroxydopamine (6-OHDA) rats.
  
  
  METHODS
  HM01 pharmacological profiles were determined in vitro and in vivo in rats. We assessed changes in fecal output and water content, and gastric emptying (GE) in 6-OHDA rats treated with orogastric (og) HM01 and L-dopa/carbidopa (LD/CD, 20/2 mg/kg). Fos immunoreactivity (ir) cells in specific brain and lumbosacral spinal cord were quantified.
  
  
  RESULTS
  HM01 displayed a high binding affinity to ghrelin receptor (Ki: 1.42 ± 0.36 nM), 4.3 ± 1.0 h half-life and high brain/plasma ratio. 6-OHDA rats had reduced daily fecal output (22%) and water intake (23%) compared to controls. HM01 (3 and 10 mg/kg) similarly reversed the decreased 4-h fecal weight and water content in 6-OHDA rats. Basal GE was not modified in 6-OHDA rats, however, LD/CD (once or daily for 8 days) delayed GE in 6-OHDA and control rats that was prevented by HM01 (3 mg/kg acute or daily before LD/CD). HM01 increased Fos-ir cell number in the area postrema, arcuate nucleus, nucleus tractus solitarius, and lumbosacral intermediolateral column of 6-OHDA rats where 6-OHDA had a lowering effect compared to controls.
  
  
  CONCLUSIONS
  6-OHDA rats display constipation- and adipsia-like features of PD and L-dopa-inhibited GE. The new orally active ghrelin agonist, HM01 crosses the blood-brain barrier and alleviates these alterations suggesting a potential benefit for PD with GI disorders.
authors.affiliation: Department of Medicine, CURE/Digestive Diseases Center, Digestive Diseases Division, University of California at Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Karasawa
authors.forename: C
authors.initials: C
authors.lastname: Pietra
authors.forename: C
authors.initials: C
authors.lastname: Giuliano
authors.forename: S
authors.initials: S
authors.lastname: Garcia-Rubio
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Yakabi
authors.forename: Y
authors.initials: Y
authors.lastname: Taché
authors.forename: L
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D001921:Brain / Q000187:drug effects*; D003248:Constipation / Q000209:etiology / Q000517:prevention & control*; D005772:Gastrointestinal Transit / Q000187:drug effects*; D054439:Ghrelin / Q000819:agonists*; D007150:Immunohistochemistry; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000978:Antiparkinson Agents; D054439:Ghrelin; D007980:Levodopa; D016627:Oxidopamine
keywords: 6-hydroxydopamine; L-dopa; Parkinson's disease; constipation; gastric emptying; ghrelin agonist