2'-Methoxy-6-methylflavone: a novel anxiolytic and sedative with subtype selective activating and modulating actions at GABA(A) receptors |
| |
Authors: | Karim Nasiara Curmi John Gavande Navnath Johnston Graham Ar Hanrahan Jane R Tierney M Louise Chebib Mary |
| |
Affiliation: | Faculty of Pharmacy A15, University of Sydney, Sydney, NSW, Australia. |
| |
Abstract: | BACKGROUND AND PURPOSEFlavonoids are known to have anxiolytic and sedative effects mediated via actions on ionotropic GABA receptors. We sought to investigate this further.EXPERIMENTAL APPROACHWe evaluated the effects of 2′-methoxy-6-methylflavone (2′MeO6MF) on native GABAA receptors in new-born rat hippocampal neurons and determined specificity from 18 human recombinant GABAA receptor subtypes expressed in Xenopus oocytes. We used ligand binding, two-electrode voltage clamp and patch clamp studies together with behavioural studies.KEY RESULTS2′MeO6MF potentiated GABA at α2β1γ2L and all α1-containing GABAA receptor subtypes. At α2β2/3γ2L GABAA receptors, however, 2′MeO6MF directly activated the receptors without potentiating GABA. This activation was attenuated by bicuculline and gabazine but not flumazenil indicating a novel site. Mutation studies showed position 265 in the β1/2 subunit was key to whether 2′MeO6MF was an activator or a potentiator. In hippocampal neurons, 2′MeO6MF directly activated single-channel currents that showed the hallmarks of GABAA Cl- currents. In the continued presence of 2′MeO6MF the single-channel conductance increased and these high conductance channels were disrupted by the γ2(381–403) MA peptide, indicating that such currents are mediated by α2/γ2-containing GABAA receptors. In mice, 2′MeO6MF (1–100 mg·kg−1; i.p.) displayed anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark tests. 2′MeO6MF induced sedative effects at higher doses in the holeboard, actimeter and barbiturate-induced sleep time tests. No myorelaxant effects were observed in the horizontal wire test.CONCLUSIONS AND IMPLICATIONS2′MeO6MF will serve as a tool to study the complex nature of the activation and modulation of GABAA receptor subtypes. |
| |
Keywords: | GABAA receptors Xenopus oocytes GABA (γ-aminobutyric acid) dissociated hippocampal neurons flavonoids anxiolytic agents sedative effects α1- and α2-containing GABAA receptors |
本文献已被 PubMed 等数据库收录! |
|