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

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-HT3 receptors (serotonin receptor subtype) in more detail: [14C]guanidinium influx into N1E-115 cells which express 5-HT3 receptors, isotonic contractions of the isolated guinea-pig ileum and equilibrium competition binding studies using a radioactively labeled 5-HT3 receptor antagonist ([3H]GR65630) (3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone). All four compounds inhibited the [14C]guanidinium influx through 5-HT3 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-HT3 receptor agonist. Both effects were concentration-dependent, with the following order of potency for both models: [6]-shogaol≥[8]-gingerol>[10]-gingerol≥[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-HT3 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 [3H]GR65630 from its binding site (5-HT3 receptor) neither on intact N1E-115 cells nor on the purified membranes of HEK-293 cells over-expressing the h5-HT3 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-HT3 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-HT3 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. [Copyright &y& Elsevier]