Biomol Ther.  2019 Nov;27(6):584-590. 10.4062/biomolther.2019.149.

Sleep Promoting Effect of Luteolin in Mice via Adenosine A1 and A2A Receptors

• Kim TH
• Custodio R
• Cheong JH
• Kim HJ
• Jung YS

• KMID: 2462886
• DOI: http://doi.org/10.4062/biomolther.2019.149

Abstract

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 receptor-benzodiazepine (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 IC₅₀ 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.

Keyword

Luteolin; Sleep; Electroencephalogram; Adenosine A1 receptor; Adenosine A2A receptor; Insomnia

MeSH Terms

Adenosine*
Animals
Binding Sites
Caffeine
Electroencephalography
Epilepsy
Eye Movements
Flumazenil
Hand
Hypnotics and Sedatives
Luteolin*
Mice*
Receptor, Adenosine A1
Receptor, Adenosine A2A
Sleep Initiation and Maintenance Disorders
Adenosine
Caffeine
Flumazenil
Hypnotics and Sedatives
Luteolin
Receptor, Adenosine A1
Receptor, Adenosine A2A