Benkherouf Ali Y, Eerola Kim, Soini Sanna L, Uusi-Oukari Mikko
Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.
Front Neurosci. 2020 Oct 14;14:594708. doi: 10.3389/fnins.2020.594708. eCollection 2020.
L. (hops) is a major constituent of beer. It exhibits neuroactive properties that make it useful as a sleeping aid. These effects are hypothesized to be mediated by an increase in GABA receptor function. In the quest to uncover the constituents responsible for the sedative and hypnotic properties of hops, recent evidence revealed that humulone, a prenylated phloroglucinol derivative comprising 35-70% of hops alpha acids, may act as a positive modulator of GABA receptors at low micromolar concentrations. This raises the question whether humulone plays a key role in hops pharmacological activity and potentially interacts with other modulators such as ethanol, bringing further enhancement in GABA receptor-mediated effects of beer. Here we assessed electrophysiologically the positive modulatory activity of humulone on recombinant GABA receptors expressed in HEK293 cells. We then examined humulone interactions with other active hops compounds and ethanol on GABA-induced displacement of [H]EBOB binding to native GABA receptors in rat brain membranes. Using BALB/c mice, we assessed humulone's hypnotic behavior with pentobarbital- and ethanol-induced sleep as well as sedation in spontaneous locomotion with open field test. We demonstrated for the first time that humulone potentiates GABA-induced currents in α1β3γ2 receptors. In radioligand binding to native GABA receptors, the inclusion of ethanol enhanced humulone modulation of GABA-induced displacement of [H]EBOB binding in rat forebrain and cerebellum as it produced a leftward shift in [H]EBOB displacement curves. Moreover, the additive modulatory effects between humulone, isoxanthohumol and 6-prenylnaringenin were evident and corresponded to the sum of [H]EBOB displacement by each compound individually. In behavioral tests, humulone shortened sleep onset and increased the duration of sleep induced by pentobarbital and decreased the spontaneous locomotion in open field at 20 mg/kg (.). Despite the absence of humulone effects on ethanol-induced sleep onset, sleep duration was increased dose-dependently down to 10 mg/kg (.). Our findings confirmed humulone's positive allosteric modulation of GABA receptor function and displayed its sedative and hypnotic behavior. Humulone modulation can be potentially enhanced by ethanol and hops modulators suggesting a probable enhancement in the intoxicating effects of ethanol in hops-enriched beer.
蛇麻草（啤酒花）是啤酒的主要成分。它具有神经活性特性，可用作助眠剂。据推测，这些作用是由γ-氨基丁酸（GABA）受体功能增强介导的。为了找出蛇麻草具有镇静和催眠特性的成分，最近有证据表明，葎草酮（一种占蛇麻草α-酸35%-70%的异戊烯基间苯三酚衍生物）在低微摩尔浓度下可能作为GABA受体的正向调节剂。这就提出了一个问题，即葎草酮在蛇麻草的药理活性中是否起关键作用，以及它是否可能与乙醇等其他调节剂相互作用，从而进一步增强啤酒中GABA受体介导的作用。在此，我们通过电生理学方法评估了葎草酮对在人胚肾293（HEK293）细胞中表达的重组GABA受体的正向调节活性。然后，我们研究了葎草酮与其他活性蛇麻草化合物以及乙醇在GABA诱导的[H]依布硒胺（EBOB）与大鼠脑膜中天然GABA受体结合的置换作用方面的相互作用。使用BALB/c小鼠，我们通过戊巴比妥和乙醇诱导的睡眠评估了葎草酮的催眠行为，并通过旷场试验评估了其在自发运动中的镇静作用。我们首次证明，葎草酮可增强α1β3γ2受体中GABA诱导的电流。在与天然GABA受体的放射性配体结合实验中，加入乙醇增强了葎草酮对GABA诱导的[H]EBOB结合置换的调节作用，因为它使[H]EBOB置换曲线向左移动。此外，葎草酮、异黄腐醇和6-异戊烯基柚皮素之间的加性调节作用明显，且与每种化合物单独引起的[H]EBOB置换之和相对应。在行为测试中，葎草酮缩短了戊巴比妥诱导的睡眠开始时间，延长了睡眠持续时间，并在20毫克/千克（.）时减少了旷场试验中的自发运动。尽管葎草酮对乙醇诱导的睡眠开始时间没有影响，但睡眠持续时间在剂量低至10毫克/千克（.）时呈剂量依赖性增加。我们的研究结果证实了葎草酮对GABA受体功能的正向变构调节作用，并展示了其镇静和催眠行为。葎草酮的调节作用可能会被乙醇和蛇麻草调节剂增强，这表明在富含蛇麻草的啤酒中，乙醇的 intoxicating 作用可能会增强。 （注：“intoxicating”直译为“令人陶醉的”，结合语境这里可能是指酒精的致醉等相关效应，但该词在医学专业语境下含义可能需结合更多背景知识准确理解，这里按原文翻译供参考。）
