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.
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.
Abdel-Aziz
Heba
H
Department of Pharmacology, Institute of Pharmaceutical and Medicinal Chemistry, Münster, Germany.
Windeck
Timo
T
Ploch
Michael
M
Verspohl
Eugen J
EJ
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002250:Carbon Radioisotopes; D002396:Catechols / Q000494:pharmacology*; D002412:Cations / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005233:Fatty Alcohols / Q000494:pharmacology*; D020939:Zingiber officinale / Q000737:chemistry; D019791:Guanidine / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism*; D007551:Isotonic Contraction / Q000187:drug effects; D008297:Male; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D014316:Tritium; D000077526:Tropisetron; D014701:Veratridine / Q000494:pharmacology
D002250:Carbon Radioisotopes; D002396:Catechols; D002412:Cations; D005233:Fatty Alcohols; D007093:Imidazoles; D007211:Indoles; D007473:Ion Channels; D027701:Organic Cation Transport Proteins; D010880:Piperidines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D015222:Sodium Channels; D014316:Tritium; C059068:GR 65630; D012701:Serotonin; D013373:Substance P; D000077526:Tropisetron; D014701:Veratridine; C040115:shogaol; C007845:gingerol; D019791:Guanidine; C083009:4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride