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GABA(A) receptor subtype selectivity underlying anxiolytic effect of 6-hydroxyflavone.

机译：GABA（A）受体亚型选择性6-羟基黄酮的抗焦虑作用。

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摘要

6-Hydroxyflavone (6HF), a naturally occurring flavonoid, was previously reported to bind to type A gamma-aminobutyric acid (GABA(A)) receptors benzodiazepine (BZ) site with moderate binding affinity. In the present study, we showed that 6HF partially potentiated GABA-induced currents in native GABA(A) receptors expressed in cortical neurons via BZ site, as the enhancement was blocked by the antagonist flumazenil. Furthermore, in patch clamp studies, 6HF displayed significant preference for alpha(2)- and alpha(3)-containing subtypes, which were thought to mediate anxiolytic effect, compared to alpha(1)- and alpha(5)-containing subtypes expressed in HEK 293T cells. In mice, 6HF exhibited anxiolytic-like effect in the elevated plus-maze test, unaccompanied at anxiolytic doses by the sedative, cognitive impairing, myorelaxant, motor incoordination and anticonvulsant effects commonly associated with classical BZs when tested in the hole-board, step-through passive avoidance, horizontal wire, rotarod, and pentylenetetrazol (PTZ)-induced seizure tests, respectively. The findings therefore identified 6HF as a promising drug candidate for the treatment of anxiety-like disorders.
机译：先前报道6-羟基黄酮（6HF）是天然存在的类黄酮，以中等的结合亲和力与A型γ-氨基丁酸（GABA（A））受体苯并二氮杂（BZ）位点结合。在本研究中，我们显示了6HF部分增强了GABA诱导的BABA部位在皮质神经元中表达的天然GABA（A）受体中的电流，因为增强作用被拮抗剂氟马西尼阻断了。此外，在膜片钳研究中，与表达的含α（1）和含α（5）的亚型相比，6HF对含α（2）和含α（3）的亚型表现出显着的偏好，这些亚型被认为可介导抗焦虑作用。在HEK 293T细胞中在小鼠中，6HF在高迷宫试验中表现出类似抗焦虑药的作用，在抗焦虑药剂量下未表现出与镇静剂，认知障碍，肌松药，运动不协调和抗惊厥作用通常伴随的经典BZs的镇静，认知障碍，抗抑郁作用。通过被动回避，水平导线，旋转脚架和戊四氮（PTZ）诱发的癫痫发作测试。因此，这些发现确定了6HF是治疗焦虑样疾病的有希望的候选药物。

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