© Georg Thieme Verlag Stuttgart · New York
Interaction of Various Piper methysticum Cultivars with CNS Receptors in vitro
June 6, 2000
October 29, 2000
31 December 2001 (online)
Methanolic leaf and root extracts of the Hawaiian kava (Piper methysticum Forst.) cultivars, Mahakea, Nene, Purple Moi and PNG, were tested on binding affinities to CNS receptors including GABAA (GABA and benzodiazepine binding site), dopamine D2, opioid (μ and δ), serotonin (5-HT6 and 5-HT7) and histamine (H1 and H2). HPLC analysis was carried out in order to determine the amount of the main kavalactones kavain, 7,8-dihydrokavain, methysticin, 7,8-dihydromethysticin, yangonin and 5,6-demethoxyyangonin. The most potent binding inhibition was observed for leaf extracts to GABAA receptors (GABA binding site) with IC50 values of approximately 3 μg/ml, whereas root extracts were less active with IC50 values ranging from 5 μg/ml (Nene) to 87 μg/ml (Mahakea). Since the leaf extracts generally contained lower amounts of the kavalactones than the root extracts, there might exist additional substances responsible for these activities. Leaf extracts also inhibited binding to dopamine D2, opioid (μ and δ) and histamine (H1 and H2) receptors more potently than the corresponding root extracts with IC50 values ranging from 1 to 100 μg/ml vs. ≥ 100 μg/l, respectively. Significant differences in the potential of binding inhibition were also observed between cultivars. Binding to serotonin (5-HT6 and 5-HT7) and benzodiazepine receptors was only weakly inhibited by both root and leaf extracts of all four cultivars. In conclusion, our investigation indicates that the GABAA, dopamine D2, opioid (μ and δ) and histamine (H1 and H2) receptors might be involved in the pharmacological action of kava extracts. Since the cultivars contained similar amounts of kavalactones, while their pharmacological activities differed markedly, other constituents may play a role in the observed activities. Additionally, leaves generally exhibited more potent binding inhibition than roots, therefore leaf of P. methysticum might be an interesting subject for further pharmacological studies.
BHK:baby hamster kidney
CHO:Chinese hamster ovary
CNS:central nervous system
3H-LSD:3 H-lysergic acid diethylamide
HPLC:high performance liquid chromatography
IC50:50 % inhibitory concentration
SFV:Semliki Forest Virus
Piper methysticum - Piperaceae - leaf extracts - root extracts - styryl pyrones - cultivars - CNS recombinant receptors
- 1 Lebot V, Merlin M, Lindstrom L.
Kava: the Pacific elexir. Healing Arts Press 1997
- 2 Singh Y N. Kava: an overview. J. Herbal Gram. 1997; 39 33-55
- 3 Hölzl J, Juretzek W, Schneider G, Stahl-Bispuk E.
Piper. In: Hänsel R, Keller K, Rimpler H, Schneider G, editors Hager's Handbuch der pharmazeutischen Praxis. Springer-Verlag 1994 Vol. 6: 191-220
- 4 Smith R M. Kava lactones in Piper methysticum from Fiji: compositions of extracts from roots, stems and leaves. Phytochemistry. 1983; 22 1055-6
- 5 Mayer H J, Kretzschmar R. Kawapyrone: Eine neuartige Substanzgruppe zentraler Muskelrelaxantien vom Typ des Mephenesins. Klinische Wochenschrift. 1966; 4 902-3
- 6 Gleitz J, Beile A, Peters T. Kavain inhibits veratridine activated voltage dependent Na(+)-channels in synaptosomes prepared from rat cerebral cortex. Neuropharmacology. 1995; 34 1133-8
- 7 Gleitz J, Beile A, Wilkens P, Ameri A, Peters T. Antithrombotic action of the kavapyrone kavain prepared from Piper methysticum on human platelets. Planta Medica. 1997; 63 27-30
- 8 Taylor C P, Meldrum B S. Na+ channels as targets for neuro-protective drugs. J. Trends in Pharmacological Sciences. 1995; 16 309-16
- 9 Bloom F E.
Neurotransmission and the central nervous system. In: Hardman JG, Limbird LE, editors The pharmacological basis of therapeutics. MacGraw-Hill Health Professions Division 1996 9th edition: pp. 267-93
- 10 Jussofie A, Schmitz A, Hiemke C. Kavapyrone-enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology. 1994; 116 469-74
- 11 Davis L P, Drew C A, Duffield P, Johnston A R, Jamieson D D. Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine sites in rodent brain. Pharmacology and Toxicology. 1992; 71 120-6
- 12 Boonen G, Häberlein H. Influence of genuine kavapyrone enantiomers on the GABAA binding site. Planta Medica. 1998; 64 504-6
- 13 Kretzschmar R.
Pharmakologische Untersuchungen zur zentralnervösen Wirkung und zum Wirkungsmechanismus der Kava-Droge (Piper methysticum Forst) und ihrer kristallinen Inhaltsstoffe. In: Rietbrock N, editor Phytopharmaka in Forschung und klinischer Anwendung. Loew 1995: 29-38
- 14 Ross S, de Freese L, Melzer M, Kolhmann R. Kava-lactone determination by a new RP-HPLC separation enabling high performance of sample analysis in aqueous solutions. Proceeding of the 46th Annual Congress of the Society for Medicinal Plant Research (GA). Vienna; 1998: 31, August - 4, September: Poster E21
- 15 Simmen U, Burkard W, Berger K, Schaffner W, Lundstrom K. Extracts and constituents of Hypericum perforatum inhibit the binding of various ligands to recombinant receptors expressed with the Semliki Forest virus system. Journal of Receptor and Transduction Research. 1999; 19 59-74
- 16 Lundstrom K, Mills A, Buell G, Allet E, Adami N, Lijiestrom P. High-level expression of the human neurokinin-1 receptor in mammalian cell lines using the Semliki Forest virus expression system. European Biochemistry. 1994; 224 197-21
- 17 Smith P K, Krohn R I, Hermanson G T, Mallia A K, Gertner F H, Provenzano M D, Fujimoto E K, Goeke N M, Olson B J, Klenk D C. Measurement of protein using bicinchoninic acid. Analytical Biochemistry. 1985; 150 76-85
- 18 Mansour A, Chalmers D T, Fox C A, Meador-Woodruff J H, Watson S J. Biochemical anatomy: insights into the cell biology and pharmacology of neurotransmitter systems in the brain. In: Schatzberg AF, Nemeroff CB, editors The American Psychiatric Press Textbook of Psychopharmacology. The American Psychiatric Press Inc. 1995: pp. 45-63
- 19 Cavadas C, Araujo I, Cotrim M D, Amaral T, Cunha A P, Macedo T, Ribeiro C F. In vitro study on the interaction of Valeriana officialis L. extracts and their amino acids on GABAA receptor in rat brain. Arzneim. Forsch.-Drug Res. 1995; 45 753-5
- 20 Nichols M.
Understanding Kava. J. Health Supplement Retailer July 1996: 44
Dr. Urs Simmen
Institute of Pharmaceutical Biology
University of Basel
Email: [email protected]
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