Dieckol, a Major Marine Polyphenol, Enhances Non-Rapid Eye Movement Sleep in Mice via the GABAA-Benzodiazepine Receptor.

Minseok Yoon,Jaekwang Lee,Jonghoon Jung,Min Young Um,Kiwon Lee,Jin-Soo Kim,Suengmok Cho,Sangwoo Seo

doi:10.3389/fphar.2020.00494

Abstract

We had previously demonstrated that phlorotannins, which are marine polyphenols, enhance sleep in mice via the GABAA-benzodiazepine (BZD) receptor. Among the constituents of phlorotannin, dieckol is a major marine polyphenol from the brown alga Ecklonia cava. Although phlorotannins are known to exert hypnotic effects, the sleep-enhancing effect of dieckol has not yet been determined. We evaluated the effect of dieckol on sleep-wake state of mice by analyzing electroencephalograms (EEGs) and electromyograms. Flumazenil, a GABAA-BZD antagonist, was used to investigate the molecular mechanism underlying the effects of dieckol on sleep. The polygraphic recordings and corresponding hypnograms revealed that dieckol accelerated the initiation of non-rapid eye movement sleep (NREMS); it shortened sleep latency and increased NREMS duration. According to the change in time-course, dieckol showed sleep-enhancing effects by increasing the amount of NREMS and decreasing wakefulness during the same hours. Additionally, sleep quality was evaluated by analyzing the EEG power density, and dieckol was found to not affect sleep intensity while zolpidem was found to reduce it. Finally, we treated mice with zolpidem or dieckol in combination with flumazenil and found the latter to inhibit the sleep-enhancing effect of dieckol and zolpidem, thereby indicating that dieckol exerts sleep-enhancing effects by activating the GABAA-BZD receptor, similar to zolpidem. These results implied that dieckol can be used as a promising herbal sleep aid with minimal side effects, unlike the existing hypnotics.

Highlights

Insomnia is a highly prevalent complaint in modern society (Jespersen et al, 2015)
Dieckol induced short sleep latency in mice, indicating that it accelerated the initiation of non-rapid eye movement sleep (NREMS), similar to zolpidem
To compare the effect of dieckol and zolpidem on sleep duration, we computed the total amounts of NREMS and rapid eye movement sleep (REMS) for 2 h after the administration of both chemicals (Figure 3C)

Summary

Introduction

Insomnia is a highly prevalent complaint in modern society (Jespersen et al, 2015). Sleep deprivation exerts negative effects on physical and mental performance, mood, as well as the immune system; overall, it affects the quality of life (Alami et al, 2018). GABAA receptors have been considered to be important molecular targets for the development of sleep-enhancing drugs and herbal sleep aids. Polyphenols, mainly flavonoids, exert their hypnotic effects through the positive allosteric modulation of GABAA receptors (Johnston, 2015). Glabrol, which is licorice component, has been characterized as a GABAA-BZD receptor ligand that exhibits hypnotic effects (Cho et al, 2012a). Many studies have been conducted to reveal the hypnotic effects of polyphenols, they have all been limited to terrestrial plants (Cho and Shimizu, 2015). We reported for the first time that phlorotannins, which are marine polyphenols, enhance sleep in mice via the GABAA-BZD receptor (Cho et al, 2014). Hypnotic effects of phlorotannins have been reported, the effect of dieckol on sleep remains to be investigated

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