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

Abstract

We had previously demonstrated that phlorotannins, which are marine polyphenols, enhance sleep in mice via the GABA A-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 sleepenhancing 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 GABA A-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 GABA A-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.

Phenolics as GABAA Receptor Ligands: An Updated Review

“…In general, phlorotannins enhanced the activity of GABA A -BZD receptors and increased GABA A R-mediated inward current in cells and increased the amplitude of GABA A -BZD receptors in primary cultured neurons, these effects being blocked by flumazenil. These results corroborate that phlorotannins are positive allosteric activators of GABA A -BZD receptors, which justifies their mechanism as sedative-hypnotics, such as dieckol or triphlorethol [ 138 , 139 , 140 ]. In the case of phlorotannins, there is a relevant clinical trial in which a phlorotannin supplement increased sleep duration scores vs. placebo and decreased wakefulness after sleep as well as the total wake time.…”

“…Dieckol was also evaluated by EEG power density, and did not affect sleep intensity, while zolpidem reduced it. Finally, the sleep-enhancing effect of dieckol and zolpidem in mice treated with zolpidem or dieckol plus flumazenil was inhibited, which confirms that dieckol exerts sleep-enhancing effects by activating the GABA A -BZD receptor [ 139 ].…”

Curcuminoids, a major turmeric component, have a sleep-enhancing effect by targeting the histamine H1 receptor

“…Our previous studies confirmed that zolpidem alters the number of bouts and sleep state transitions, similar to curcuminoids-induced sleep. 25,26 In contrast, curcuminoids increased the EEG delta activity in NREMS. This differs from sleeping pills such as benzodiazepines, which alter sleep architecture by reducing NREMS.…”

In silico investigation and potential therapeutic approaches of natural products for COVID-19: Computer-aided drug design perspective

“…Finally, they were saved as pdb format for further investigation such as molecular docking and ADMET. A preliminary dose of 1.5 mg was given, followed by 0.5 mg twice daily for the next 7 days, and then 0.5 mg once daily until the 14-day treatment was completed Secondly, the reported Ligand (L05) Dieckol (Yoon et al, 2020), (L14) Amentoflavone (Kim et al, 1998), (L17) Pectolinarin (Cheriet et al, 2020), (L18) Rhoifolin (Xiong et al, 2021) all belong to classes of flavonoid. As they are the same classes of compounds, this could be probable reason for their similar or nearly similar energy binding.…”

“…Secondly, the reported Ligand (L05) Dieckol ( Yoon et al., 2020 ), (L14) Amentoflavone ( Kim et al., 1998 ), (L17) Pectolinarin ( Cheriet et al., 2020 ), (L18) Rhoifolin ( Xiong et al., 2021 ) all belong to classes of flavonoid. As they are the same classes of compounds, this could be probable reason for their similar or nearly similar energy binding.…”