To overcome the adverse effects of sleep medications, special attention has been recently focused on alternative sleep aids such as natural and herbal therapies ( Cho et al., 2012). However, long-term use of these drugs have been demonstrated to often result in tolerance and dependence, thus leading to withdrawal syndrome following their discontinuation ( Rudolph and Knoflach, 2011). To improve sleep quality, most elderly people with insomnia are known to take hypnotic agents such as benzodiazepines, antidepressants, and antihistamines ( Bloom et al., 2009). The most common case among sleep disturbances that affect elderly people is insomnia worldwide ( Neikrug and Ancoli-Israel, 2010). Thus, improvement of sleep quality, especially among elderly people, is considered to be essential care issues. Studies have shown that the prevalence of sleep disorders increase with age so that almost up to 50% of elderly people (>65 yr) suffer from sleep disturbances ( Rashid et al., 2012). Sleep is essential to maintain human health and well-being, and sleep disturbances can affect negatively both physical and psychological health ( Krueger et al., 2008). Keywords: Luteolin, Sleep, Electroencephalogram, Adenosine A1 receptor, Adenosine A2A receptor, Insomnia From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding. However, luteolin did not bind to either BDZ-receptor or GABAAR. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with IC 50 of 1.19, 0.84 μg/kg, respectively. 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. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptor-benzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. However, little information is available regarding the hypnotic effect of luteolin. Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer’s disease.
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