Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum

Eur J Pharmacol. 2006 Jan 13;530(1-2):136-43. doi: 10.1016/j.ejphar.2005.10.049. Epub 2005 Dec 20.

Abstract

Ginger (rhizomes of Zingiber officinale) has been shown to exert potent anti-emetic properties, but its mode of action has not yet been elucidated. Among its active constituents, [6]-, [8]- and [10]-gingerol as well as [6]-shogaol were shown in different in vivo studies to be at least partly responsible for the drug's anti-emetic properties. In an attempt to gain more insight into the mode of action of these compounds, three different in vitro models were used to investigate their effects on 5-HT(3) receptors (serotonin receptor subtype) in more detail: [(14)C]guanidinium influx into N1E-115 cells which express 5-HT(3) receptors, isotonic contractions of the isolated guinea-pig ileum and equilibrium competition binding studies using a radioactively labeled 5-HT(3) receptor antagonist ([(3)H]GR65630) (3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone). All four compounds inhibited the [(14)C]guanidinium influx through 5-HT(3) receptor channels as well as contractions of the guinea-pig ileum induced by SR57227A ((4-amino)-(6-chloro-2-pyridyl)l-piperidine hydrochloride), a highly selective 5-HT(3) receptor agonist. Both effects were concentration-dependent, with the following order of potency for both models: [6]-shogaol> or =[8]-gingerol>[10]-gingerol> or =[6]-gingerol. All compounds showed also weak anticholinergic and antineurokininergic activities in the guinea-pig ileum (acetylcholine and substance P are mediators of the 5-HT(3) receptor effect). The vanilloid receptor did not seem to be involved derived from experiments using capsazepine. None of the tested ginger substances, however, was able to displace [(3)H]GR65630 from its binding site (5-HT(3) receptor) neither on intact N1E-115 cells nor on the purified membranes of HEK-293 cells over-expressing the h5-HT(3) receptor. It may be concluded that [6]-, [8]-, [10]-gingerol and [6]-shogaol exert their anti-emetic effect at least partly by acting on the 5-HT(3) receptor ion-channel complex, probably by binding to a modulatory site distinct from the serotonin binding site. This may include indirect effects via receptors in the signal cascade behind the 5-HT(3) receptor channel complex such as substance P receptors and muscarinic receptors; this needs further investigation since ginger is effective against motion sickness which is cured by some vanilloids and by anticholinergics such as scopolamine.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • Carbon Radioisotopes
  • Catechols / pharmacology*
  • Cations / metabolism
  • Cations / pharmacology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Fatty Alcohols / pharmacology*
  • Ginger / chemistry
  • Guanidine / pharmacology
  • Guinea Pigs
  • Humans
  • Ileum / drug effects*
  • Ileum / physiology
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Indoles / metabolism
  • Indoles / pharmacology
  • Ion Channels / metabolism*
  • Isotonic Contraction / drug effects
  • Male
  • Mice
  • Organic Cation Transport Proteins / metabolism
  • Piperidines / antagonists & inhibitors
  • Piperidines / pharmacology
  • Receptors, Serotonin, 5-HT3 / metabolism*
  • Serotonin / pharmacology
  • Serotonin 5-HT3 Receptor Antagonists
  • Serotonin Antagonists / pharmacology
  • Sodium Channels / metabolism
  • Substance P / pharmacology
  • Tritium
  • Tropisetron
  • Veratridine / pharmacology

Substances

  • Carbon Radioisotopes
  • Catechols
  • Cations
  • Fatty Alcohols
  • Imidazoles
  • Indoles
  • Ion Channels
  • Organic Cation Transport Proteins
  • Piperidines
  • Receptors, Serotonin, 5-HT3
  • Serotonin 5-HT3 Receptor Antagonists
  • Serotonin Antagonists
  • Sodium Channels
  • Tritium
  • GR 65630
  • Serotonin
  • Substance P
  • Tropisetron
  • Veratridine
  • shogaol
  • gingerol
  • Guanidine
  • 4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride