Ginger and its pungent constituents non-competitively inhibit activation of human recombinant and native 5-HT3 receptors of enteric neurons

Neurogastroenterol Motil. 2013 May;25(5):439-47, e302. doi: 10.1111/nmo.12107. Epub 2013 Mar 12.

Abstract

Background: Beneficial effects of ginger in the treatment of gastrointestinal (GI) problems and chemotherapy-induced nausea and vomiting are well accepted. In rodents, the action of ginger seems to be mediated by the inhibition of 5-HT3 receptors, which are established targets to combat emesis and irritable bowel syndrome.

Methods: Heterologously expressed human 5-HT3 A or 5-HT3 AB receptors were characterized by means of Ca(2+) influx studies using HEK293 cells. Complementing Ca(2+) measurements in Fluo-4-AM-stained whole-mount preparations of the human submucous plexus were carried out. Furthermore, [3H]GR65630 binding assays were performed to reveal the mode of action of ginger and its pungent compounds.

Key results: We show for the first time that ginger extracts and its pungent arylalkane constituents concentration-dependently inhibit activation of human 5-HT3 receptors. Ginger extracts inhibited both receptors with increasing content of pungent compounds, confirming that these are part of ginger's active principle. Inhibition potencies of the arylalkanes 6-gingerol and 6-shogaol on both receptors were in the low micromolar range. A lipophilic ginger extract and 6-gingerol had no influence on 5-HT potency, but reduced the 5-HT maximum effect, indicating non-competitive inhibition. The non-competitive action was confirmed by [(3) H]GR65630 binding, showing that the ginger extract did not displace the radioligand from 5-HT3 A and 5-HT3 AB receptors. The potential relevance of the inhibitory action of ginger on native 5-HT3 receptors in the gut was confirmed in whole-mount preparations of the human submucous plexus. While a general neurotoxic effect of 6-gingerol was ruled out, it inhibited the 2-methyl-5-HT-mediated activation of 5-HT3 receptors residing on enteric neurons.

Conclusions & inferences: Our findings may encourage the use of ginger extracts to alleviate nausea in cancer patients receiving chemotherapy and to treat functional GI disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catechols / pharmacology*
  • Fatty Alcohols / pharmacology*
  • HEK293 Cells
  • Humans
  • Neurons / drug effects*
  • Neurons / metabolism
  • Plant Extracts / pharmacology*
  • Receptors, Serotonin, 5-HT3 / metabolism
  • Recombinant Proteins / metabolism
  • Serotonin 5-HT3 Receptor Antagonists / pharmacology*
  • Submucous Plexus / drug effects*
  • Submucous Plexus / metabolism
  • Zingiber officinale / chemistry

Substances

  • Catechols
  • Fatty Alcohols
  • Plant Extracts
  • Receptors, Serotonin, 5-HT3
  • Recombinant Proteins
  • Serotonin 5-HT3 Receptor Antagonists
  • gingerol