Kim Tae-Ho, Custodio Raly James, Cheong Jae Hoon, Kim Hee Jin, Jung Yi-Sook
College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
Uimyoung Research Institute in Neuroscience, Sahmyook University, Seoul 01795, Republic of Korea.
Biomol Ther (Seoul). 2019 Nov 1;27(6):584-590. doi: 10.4062/biomolther.2019.149.
Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer's disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptorbenzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with IC of 1.19, 0.84 μg/kg, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.
木犀草素是一种广泛存在的黄酮类化合物，已知其对多种神经系统疾病如癫痫和阿尔茨海默病具有神经保护活性。然而，关于木犀草素的催眠作用的信息却很少。在本研究中，我们评估了木犀草素的催眠作用及其潜在机制。在戊巴比妥诱导的睡眠小鼠模型中，木犀草素（1和3毫克/千克，口服）缩短了睡眠潜伏期并增加了总睡眠时间。通过脑电图（EEG）和肌电图（EMG）记录，我们证明木犀草素增加了非快速眼动（NREM）睡眠时间并减少了清醒时间。为了评估潜在机制，我们研究了各种药理学拮抗剂对木犀草素催眠作用的影响。3毫克/千克木犀草素的催眠作用不受氟马西尼（一种GABAA受体 - 苯二氮䓬（GABAAR - BDZ）结合位点拮抗剂）和荷包牡丹碱（一种GABAAR - GABA结合位点拮抗剂）的影响。另一方面，3毫克/千克木犀草素的催眠作用几乎被咖啡因（一种腺苷A1和A2A受体（A1R和A2AR）的拮抗剂）、8 - 环戊基 - 1,3 - 二丙基黄嘌呤（DPCPX，一种A1R拮抗剂）和SCH - 58261（一种A2AR拮抗剂）完全阻断。从结合亲和力测定中，我们发现木犀草素不仅与A1R有显著结合，而且与A2AR也有显著结合，其IC分别为1.19、0.84微克/千克。然而，木犀草素与BDZ受体或GABAAR均无结合。从这些结果表明，木犀草素通过与A1R和A2AR结合具有催眠功效。
