New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson's disease

Neurogastroenterol Motil. 2014 Dec;26(12):1771-82. doi: 10.1111/nmo.12459. Epub 2014 Oct 19.


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.

Key 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 & inferences: 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.

Keywords: 6-hydroxydopamine; L-dopa; Parkinson's disease; constipation; gastric emptying; ghrelin agonist.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiparkinson Agents / adverse effects
  • Brain / drug effects*
  • Constipation / etiology
  • Constipation / prevention & control*
  • Gastrointestinal Transit / drug effects*
  • Ghrelin / agonists*
  • Immunohistochemistry
  • Levodopa / adverse effects
  • Male
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / complications*
  • Rats
  • Rats, Sprague-Dawley


  • Antiparkinson Agents
  • Ghrelin
  • Levodopa
  • Oxidopamine