title: Hypnotic effects and GABAergic mechanism of licorice (Glycyrrhiza glabra) ethanol extract and its major flavonoid constituent glabrol.
abstract: Licorice (Glycyrrhiza glabra, GG) is one of the most frequently used herbal medicines worldwide, and its various biological activities have been widely studied. GG is reported to have neurological properties such as antidepressant, anxiolytic, and anticonvulsant effects. However, its hypnotic effects and the mechanism of GG and its active compounds have not yet been demonstrated. In this study, GG ethanol extract (GGE) dose-dependently potentiated pentobarbital-induced sleep and increased the amount of non-rapid eye movement sleep in mice without decreasing delta activity. The hypnotic effect of GGE was completely inhibited by flumazenil, which is a well-known γ-aminobutyric acid type A-benzodiazepine (GABA(A)-BZD) receptor antagonist, similar to other GABA(A)-BZD receptor agonists (e.g., diazepam and zolpidem). The major flavonoid glabrol was isolated from the flavonoid-rich fraction of GGE; it inhibited [(3)H] flumazenil binding to the GABA(A)-BZD receptors in rat cerebral cortex membrane with a binding affinity (K(i)) of 1.63 μM. The molecular structure and pharmacophore model of glabrol and liquiritigenin indicate that the isoprenyl groups of glabrol may play a key role in binding to GABA(A)-BZD receptors. Glabrol increased sleep duration and decreased sleep latency in a dose-dependent manner (5, 10, 25, and 50mg/kg); its hypnotic effect was also blocked by flumazenil. The results imply that GGE and its flavonoid glabrol induce sleep via a positive allosteric modulation of GABA(A)-BZD receptors.
authors.affiliation: Korea Food Research Institute, Sungnam 463-746, Republic of Korea.
authors.forename: Suengmok
authors.initials: S
authors.lastname: Cho
authors.forename: Ji-Hae
authors.initials: JH
authors.lastname: Park
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.forename: Daeseok
authors.initials: D
authors.lastname: Han
authors.forename: Dongsoo
authors.initials: D
authors.lastname: Kim
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Cho
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yang
authors.forename: Minseok
authors.initials: M
authors.lastname: Yoon
authors.forename: Changho
authors.initials: C
authors.lastname: Lee
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
authors.forename: Nam-In
authors.initials: NI
authors.lastname: Baek
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000737:chemistry; D005133:Eye Movements / Q000187:drug effects; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology; D006035:Glycyrrhiza / Q000737:chemistry*; D006993:Hypnotics and Sedatives / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010424:Pentobarbital / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D028321:Plant Preparations; D011963:Receptors, GABA-A / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects
chemical_list: D044950:Flavanones; D005419:Flavonoids; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D008024:Ligands; D010936:Plant Extracts; D028321:Plant Preparations; D011963:Receptors, GABA-A; D000431:Ethanol; D005442:Flumazenil; C420863:glabrol; D010424:Pentobarbital; C083152:liquiritigenin