Positive allosteric modulation of native and recombinant GABAA receptors by hops prenylflavonoids
Hops are a major component of beer that is added during brewing. In addition to its wide range of bioactivity, it exhibits neuroactive properties as a sedative and sleeping aid. The compounds responsible for this activity are yet to be revealed and understood in terms of their pharmacological proper...
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Published in | European journal of pharmacology Vol. 852; pp. 34 - 41 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
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Elsevier B.V
05.06.2019
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Abstract | Hops are a major component of beer that is added during brewing. In addition to its wide range of bioactivity, it exhibits neuroactive properties as a sedative and sleeping aid. The compounds responsible for this activity are yet to be revealed and understood in terms of their pharmacological properties. Here we evaluated the potential of several hops flavonoids in modulating the GABAergic activity and assessed their selectivity to GABAA receptors subtypes. GABA-potentiating effects were measured using [3H]ethynylbicycloorthobenzoate (EBOB) radioligand binding assay in native and recombinant α1β3γ2, α2β3γ2 and α6β3δ receptors expressed in HEK293 cells. Flumazenil sensitivity of GABA-potentiating effects and [3H]Ro 15-4513 binding assay were used to examine the flavonoids binding to benzodiazepine site. The prenylflavonoids xanthohumol (XN), isoxanthohumol (IXN) and 8-prenylnaringenin (8PN) potentiated GABA-induced displacement of [3H]EBOB binding in a concentration-dependent manner. The IC50 for this potentiation in native GABAA receptors were 29.7 µM, 11.6 µM, 7.3 µM, respectively. In recombinant receptors, the sensitivity to prenylflavonoid potentiation of GABA-induced displacement of [3H]EBOB binding followed the order α6β3δ > α2β3γ2 > α1β3γ2 with the strongest inhibition observed by 8PN in α6β3δ (IC50 = 3.6 μM). Flumazenil had no significant effect on the prenylflavonoid-induced displacement of [3H]EBOB binding and [3H]Ro 15-4513 displacement from native GABAA receptors was only detected at high micromolar concentrations (100 µM). We identified potent prenylflavonoids in hops that positively modulate GABA-induced responses in native and αβγ/δ recombinant GABAA receptors at low micromolar concentrations. These GABAergic modulatory effects were not mediated via the high-affinity benzodiazepine binding site. |
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AbstractList | Hops are a major component of beer that is added during brewing. In addition to its wide range of bioactivity, it exhibits neuroactive properties as a sedative and sleeping aid. The compounds responsible for this activity are yet to be revealed and understood in terms of their pharmacological properties. Here we evaluated the potential of several hops flavonoids in modulating the GABAergic activity and assessed their selectivity to GABAA receptors subtypes. GABA-potentiating effects were measured using [3H]ethynylbicycloorthobenzoate (EBOB) radioligand binding assay in native and recombinant α1β3γ2, α2β3γ2 and α6β3δ receptors expressed in HEK293 cells. Flumazenil sensitivity of GABA-potentiating effects and [3H]Ro 15-4513 binding assay were used to examine the flavonoids binding to benzodiazepine site. The prenylflavonoids xanthohumol (XN), isoxanthohumol (IXN) and 8-prenylnaringenin (8PN) potentiated GABA-induced displacement of [3H]EBOB binding in a concentration-dependent manner. The IC50 for this potentiation in native GABAA receptors were 29.7 µM, 11.6 µM, 7.3 µM, respectively. In recombinant receptors, the sensitivity to prenylflavonoid potentiation of GABA-induced displacement of [3H]EBOB binding followed the order α6β3δ > α2β3γ2 > α1β3γ2 with the strongest inhibition observed by 8PN in α6β3δ (IC50 = 3.6 μM). Flumazenil had no significant effect on the prenylflavonoid-induced displacement of [3H]EBOB binding and [3H]Ro 15-4513 displacement from native GABAA receptors was only detected at high micromolar concentrations (100 µM). We identified potent prenylflavonoids in hops that positively modulate GABA-induced responses in native and αβγ/δ recombinant GABAA receptors at low micromolar concentrations. These GABAergic modulatory effects were not mediated via the high-affinity benzodiazepine binding site. |
Author | Soini, Sanna L. Uusi-Oukari, Mikko Stompor, Monika Benkherouf, Ali Y. |
Author_xml | – sequence: 1 givenname: Ali Y. orcidid: 0000-0002-3155-0991 surname: Benkherouf fullname: Benkherouf, Ali Y. organization: Centre of Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Finland – sequence: 2 givenname: Sanna L. surname: Soini fullname: Soini, Sanna L. organization: Centre of Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Finland – sequence: 3 givenname: Monika surname: Stompor fullname: Stompor, Monika organization: Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszów, Poland – sequence: 4 givenname: Mikko surname: Uusi-Oukari fullname: Uusi-Oukari, Mikko email: mikko.uusi-oukari@utu.fi organization: Centre of Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Finland |
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Keywords | Flavonoids Pharmacodynamics Allosteric modulation Radioligand binding Humulus lupulus GABAA receptors |
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Snippet | Hops are a major component of beer that is added during brewing. In addition to its wide range of bioactivity, it exhibits neuroactive properties as a sedative... |
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SubjectTerms | Allosteric modulation Flavonoids GABAA receptors Humulus lupulus Pharmacodynamics Radioligand binding |
Title | Positive allosteric modulation of native and recombinant GABAA receptors by hops prenylflavonoids |
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