Hypnotic effects and GABAergic mechanism of licorice (Glycyrrhiza glabra) ethanol extract and its major flavonoid constituent glabrol

Suengmok Cho; Ji Hae Park; Ae Nim Pae; Daeseok Han; Dongsoo Kim; Nam Chul Cho; Kyoung Tai No; Hyejin Yang; Minseok Yoon; Changho Lee; Makoto Shimizu; Nam In Baek

doi:10.1016/j.bmc.2012.04.011

Hypnotic effects and GABAergic mechanism of licorice (Glycyrrhiza glabra) ethanol extract and its major flavonoid constituent glabrol

Suengmok Cho, Ji Hae Park, Ae Nim Pae, Daeseok Han, Dongsoo Kim, Nam Chul Cho, Kyoung Tai No, Hyejin Yang, Minseok Yoon, Changho Lee, Makoto Shimizu, Nam In Baek

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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 [ ³H] 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 50 mg/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.

Original language	English
Pages (from-to)	3493-3501
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	11
DOIs	https://doi.org/10.1016/j.bmc.2012.04.011
Publication status	Published - 2012 Jun 1

Bibliographical note

Funding Information:
This study was supported by a Grant from the Korea Food Research Institute (Project No. E0112402). Pharmacophore research was supported by Korea Institute of Science and Technology. The first author wishes to thank the Japanese Society for Promotion of Science (JSPS) for a RONPAKU (Dissertation Ph.D program) Fellowship at the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo.

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2012.04.011

Cite this

Cho, S., Park, J. H., Pae, A. N., Han, D., Kim, D., Cho, N. C., No, K. T., Yang, H., Yoon, M., Lee, C., Shimizu, M., & Baek, N. I. (2012). Hypnotic effects and GABAergic mechanism of licorice (Glycyrrhiza glabra) ethanol extract and its major flavonoid constituent glabrol. Bioorganic and Medicinal Chemistry, 20(11), 3493-3501. https://doi.org/10.1016/j.bmc.2012.04.011

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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 [ 3H] 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 50 mg/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.",

author = "Suengmok Cho and Park, {Ji Hae} and Pae, {Ae Nim} and Daeseok Han and Dongsoo Kim and Cho, {Nam Chul} and No, {Kyoung Tai} and Hyejin Yang and Minseok Yoon and Changho Lee and Makoto Shimizu and Baek, {Nam In}",

note = "Funding Information: This study was supported by a Grant from the Korea Food Research Institute (Project No. E0112402). Pharmacophore research was supported by Korea Institute of Science and Technology. The first author wishes to thank the Japanese Society for Promotion of Science (JSPS) for a RONPAKU (Dissertation Ph.D program) Fellowship at the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo.",

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T1 - Hypnotic effects and GABAergic mechanism of licorice (Glycyrrhiza glabra) ethanol extract and its major flavonoid constituent glabrol

AU - Cho, Suengmok

AU - Park, Ji Hae

AU - Pae, Ae Nim

AU - Han, Daeseok

AU - Kim, Dongsoo

AU - Cho, Nam Chul

AU - No, Kyoung Tai

AU - Yang, Hyejin

AU - Yoon, Minseok

AU - Lee, Changho

AU - Shimizu, Makoto

AU - Baek, Nam In

N1 - Funding Information: This study was supported by a Grant from the Korea Food Research Institute (Project No. E0112402). Pharmacophore research was supported by Korea Institute of Science and Technology. The first author wishes to thank the Japanese Society for Promotion of Science (JSPS) for a RONPAKU (Dissertation Ph.D program) Fellowship at the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo.

PY - 2012/6/1

Y1 - 2012/6/1

N2 - 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 [ 3H] 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 50 mg/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.

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Hypnotic effects and GABAergic mechanism of licorice (Glycyrrhiza glabra) ethanol extract and its major flavonoid constituent glabrol

Abstract

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