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Mode of Action of Peppermint Oil and (-)-Menthol with Respect to 5-HT3 Receptor Subtypes

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Mode of Action of Peppermint Oil and (-)-Menthol with Respect to 5-HT3 Receptor Subtypes Mode of action of peppermint oil and (-)-menthol with respect to 5-HT3 receptor subtypes: binding studies, cation uptake by receptor channels and contraction of isolated rat ileum Eugen J Verspohl To cite this version: Eugen J Verspohl. Mode of action of peppermint oil and (-)-menthol with respect to 5-HT3 receptor subtypes: binding studies, cation uptake by receptor channels and contraction of isolated rat ileum. Phytotherapy Research, Wiley, 2010, 10.1002/ptr.3316. hal-00599827 HAL Id: hal-00599827 https://hal.archives-ouvertes.fr/hal-00599827 Submitted on 11 Jun 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Phytotherapy Research Mode of action of peppermint oil and (-)-menthol with respect to 5-HT3 receptor subtypes: binding studies, cation uptake by receptor channels and contraction of isolated rat ileum ForJournal: Phytotherapy Peer Research Review Manuscript ID: PTR-09-0443.R1 Wiley - Manuscript type: Full Paper Date Submitted by the 24-Aug-2010 Author: Complete List of Authors: Verspohl, Eugen; Institute of Pharmaceutical and Medicinal Chemistry, Pharmacology Keyword: Peppermint oil, (-)-Menthol, 5-HT3 receptor http://mc.manuscriptcentral.com/ptr Page 1 of 20 Phytotherapy Research Pfefferminz #10 Revised 24/08/2010 1 1 2 3 4 5 6 7 Mode of action of peppermint oil and (-)-menthol with respect to 5-HT 3 8 9 receptor subtypes: binding studies, cation uptake by 10 receptor channels and contraction of isolated rat ileum 11 12 13 14 15 16 Heimes, Katharina, Hauk, Florian, Verspohl, Eugen J. 17 18 19 1Department of Pharmacology, Institute of Pharmaceutical and Medicinal Chemistry, 20 For Peer Review 21 Hittorfstr. 58-62, 48149 Münster, Germany 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Address for correspondence: 36 37 38 39 Dr. E.J. Verspohl 40 41 Dept. Pharmacology (Institute of Pharmaceutical and Medicinal Chemistry) 42 Hittorfstr. 58-62 43 44 48149 Münster, Germany 45 46 *49/(0)251/83-33339 47 48 49 50 51 52 53 54 55 56 57 58 59 60 http://mc.manuscriptcentral.com/ptr Phytotherapy Research Page 2 of 20 Pfefferminz #10 Revised 24/08/2010 2 1 2 3 4 5 ABSTRACT 6 7 8 Peppermint oil (Mentha x piperita L. ( Lamiaceae )) has been shown to exert potent anti- 9 10 emetic properties, but its mode of action has not yet been elucidated. Among its active 11 12 constituents (-)-menthol is most important. Three different in vitro models were used to 14 13 investigate the effects on 5-HT 3 receptors (serotonin receptor subtype): [ C]guanidinium 14 15 influx into N1E-115 cells which express 5-HT 3 receptors, isotonic contractions of the isolated 16 rat ileum and equilibrium competition binding studies using a radioactively labelled 5-HT 17 3 18 receptor antagonist ([ 3H]GR65630) (3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3- 19 14 20 yl)-1-propanone). BothFor peppermint Peer oil and (-)-menth Reviewol inhibited [ C]guanidinium influx 21 through 5-HT 3 receptor channels as well as contractions of the ileum induced by serotonin. 22 23 Neither the peppermint oil nor (-)-menthol, however, was able to displace [ 3H]GR65630 from 24 25 5-HT 3 binding sites. It may be concluded that peppermint oil and (-)-menthol exert their anti- 26 emetic effect at least partly by acting on the 5-HT 3 receptor ion-channel complex, probably by 27 28 binding to a modulatory site distinct from the serotonin binding site. 29 30 31 32 33 Index words: Peppermint oil, (-)-menthol, 5-HT 3 receptor 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 http://mc.manuscriptcentral.com/ptr Page 3 of 20 Phytotherapy Research Pfefferminz #10 Revised 24/08/2010 3 1 2 3 4 5 1. INTRODUCTION 6 7 8 Peppermint (Mentha x piperita L. (Lamiaceae)) contains 0.5 – 4 % volatile oil with the main 9 10 component (-)-menthol. The volatile oil should consist of 30 – 55 % (-)-menthol. Peppermint 11 has numerous effects. A tea is used against acute and chronic gastritis, enteritis, 12 13 disturbances of the GI-tract and gall bladder. An antispasmodic effect of an ethanolic 14 15 peppermint extract was observed: contractions of guinea pig ileum induced by acetylcholine 16 and histamine were inhibited (Forster et al., 1980). The mechanism of action of menthol was 17 18 investigated (Della Loggia et al., 1990). For the antispasmodic effect of menthol partly a Ca- 19 channel modifying effect was observed (Grigoleit and Grigoleit 2005a). 20 For Peer Review 21 22 23 (-)-Menthol, menthon and similar compounds stereoselectively modulate the ionotropic 24 channels of GABA - und glycin receptors (Hall et al., 2004). Since it influences gastric 25 A 26 motility, it is used against IBS (irritable bowel syndrome) (Grigoleit and Grigoleit 2005a). 27 ® 28 Acid-resistant preparations (e.g. Colpermin ) are marketed and daily doses of 3 times 0.2 – 29 0.4 mL peppermint oil are used. It is combined in many preparations for its effect as a 30 31 carminative, cholagoge or sedative. It is marketed as a prokinetic, e.g. Carminativum- 32 ® 33 Hetterich , which includes additional constituents. 34 35 36 Topical (-)-menthol induces a sensation of coldness by which itching (urticaria and pruritus) 37 and pain are reduced. This effect is mediated by the activation of TRPM8 receptors (Peier et 38 39 al., 2002). Topically applicated peppermint oil is also used against migraine and tension 40 41 headache. 42 43 44 In the context of this paper most importantly peppermint tea is used as an antiemetic; the 45 46 mechanism of this action is not fully understood. It is a remedy in pregnant women besides 47 ginger and cannabis (Westfall 2004). Interestingly 5-HT 3-receptor antagonists, 5-HT 4 48 49 receptor agonists and anticholinergics are not showing a better effect than peppermint oil. 50 51 52 Recently the ability was shown for ginger extracts and some of its compounds to inhibit 5- 53 14 54 HT 3 mediated [ C]guanidinium influx into N1E-115 cells (Abdel-Aziz et al., 2005). Based on 55 these results, the present work describes similar experiments to elucidate the possible mode 56 57 of antiemetic action of peppermint oil and (-)-menthol with respect to 5-HT 3 receptors. Since 58 59 5-HT 3 receptors are also involved in the pathogenesis of IBS, a disease already mentioned 60 above, the outcome could also help to understand the peppermint oil effectiveness in this http://mc.manuscriptcentral.com/ptr Phytotherapy Research Page 4 of 20 Pfefferminz #10 Revised 24/08/2010 4 1 2 3 disease. It was therefore, aimed to investigate a possible interaction of peppermint oil and of 4 5 (-)-menthol with the 5-HT 3-receptor channel system. 6 7 8 9 10 11 2. MATERIALS AND METHODS 12 13 14 15 16 2.1 Materials 17 18 The peppermint oil was from Caelo, Hilden (Germany) and (-)-mernthol from Fluka, Buchs 19 20 (Switzerland). SerotoninFor creatinine Peer sulphate monohydr Reviewate (5-HT) was from Fluka, Germany, 21 veratridine and acetylcholine from Sigma-Aldrich, Steinheim (Germany). Tropisetron was a 22 23 gift from Novartis, Basel (Switzerland). SR57227A ((4-amino)-(6-chloro-2-pyridyl)L-piperidine 24 14 25 hydrochloride) was purchased from Tocris, UK, [ C]guanidinium HCl from Biotrend, Cologne 26 (Germany) (specific activity: 55 mCi/mmol) and [ 3H]GR65630 (3-(5-methyl-1H-imidazol-4-yl)- 27 28 1-(1-methyl-1H-indol-3-yl)-1-propanone) from Perkin-Elmer, Boston (USA) (specific activity: 29 30 85.5 mCi/mmol). 31 32 33 34 2.2 Preparation of Solutions 35 36 37 The peppermint oil and (-)-menthol were dissolved in DMSO (dimethylsulfoxide) and then 38 39 diluted to the required concentration with the respective assay buffer. The final concentration 40 41 of DMSO in any of the experiments was less than 0.3 %. In this concentration (and in a 10- 42 fold higher one) DMSO did not show any effect on either test system used. Veratridine, which 43 + 44 was used as a control agent to activate fast voltage gated Na channels, was dissolved in 45 ethanol and then diluted to the required concentration with assay buffer (final concentration 46 47 of ethanol was 1 %). Ethanol was shown not to affect the veratridine-induced 48 [14 C]guanidinium influx into N1E-115 cells (Barann et al., 1995), and, therefore, 1 % ethanol 49 14 50 was used in the experiments with [ C]guanidinium and veratridine. All other substances 51 were dissolved directly in the respective assay buffer. 52 53 54 55 2.3 N1E-115 Cell Culture 56 57 58 Mouse neuroblastoma cells of the clone N1E-115 express 5-HT 3 receptors (Bönisch et al., 59 60 1993). Passage numbers 40-70 were grown in Dulbecco’s modified Eagle’s medium (DMEM) containing sodium pyruvate, glucose (1000 mg/L) and pyridoxine; the growth medium was supplemented with penicillin (100 I.U./mL), streptomycin (100 µg/mL) and 10 % foetal calf http://mc.manuscriptcentral.com/ptr Page 5 of 20 Phytotherapy Research Pfefferminz #10 Revised 24/08/2010 5 1 2 3 serum (PAA, Colbe, Germany).
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