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Marine polyphenol phlorotannins promote non-rapid eye movement sleep in mice via the benzodiazepine site of the GABAA receptor

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Abstract

Rationale

In psychopharmacology, researchers have been interested in the hypnotic effects of terrestrial plant polyphenols and their synthetic derivatives. Phlorotannins, a marine plant polyphenol, could have potential as a source of novel hypnotic drugs.

Objectives

The effects of phlorotannins and major phlorotannin constituent eckstolonol on sleep–wake profiles in mice were evaluated in comparison with diazepam, and their hypnotic mechanism was also investigated.

Methods

The effects of phlorotannin preparation (PRT) and eckstolonol orally given on sleep–wake profiles were measured by recording electroencephalograms (EEG) and electromyograms in C57BL/6N mice. Flumazenil, a GABAA-benzodiazepine (BZD) receptor antagonist, was injected 15 min before PRT and eckstolonol to reveal its hypnotic mechanism.

Results

PRT administration (>250 mg/kg) produced a significant decrease in sleep latency and an increase in the amount of non-rapid eye movement sleep (NREMS). Eckstolonol significantly decreased sleep latency (>12.5 mg/kg) and increased the amount of NREMS (50 mg/kg). PRT and eckstolonol had no effect on EEG power density of NREMS. The hypnotic effects of PRT or eckstolonol were completely abolished by pretreatment with flumazenil.

Conclusions

We demonstrated that phlorotannins promote NREMS by modulating the BZD site of the GABAA receptor. These results suggest that phlorotannins can be potentially used as an herbal medicine for insomnia and as a promising structure for developing novel sedative–hypnotics.

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Acknowledgments

This study was supported by grants from the Korea Food Research Institute (E0131402), Small and Medium Business Administration (G01981), the National Basic Research Program of China (2011CB711000, 2009ZX09303-006), the National Natural Science Foundation of China (31171010, 31121061, 31271164), the Shanghai Committee of Science and Technology (13140903100, 13dz2260700), and the Shanghai Leading Academic Discipline Project (B119).

Conflict of interest

All authors declare no conflicts of interest and had no disclosures.

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Authors and Affiliations

  1. Korea Food Research Institute, Sungnam, 463-746, Republic of Korea

    Suengmok Cho, Minseok Yoon, Hyejin Yang & Jiyoung Kim

  2. Department of Seafood Science and Technology, Institute of Marine Industry, Gyeongsang National University, Tongyeong, 650-160, Republic of Korea

    Minseok Yoon & Jin-Soo Kim

  3. Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 136-791, Republic of Korea

    Ae Nim Pae & Nam-Chul Cho

  4. International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan

    Yohko Takata & Yoshihiro Urade

  5. Department of Physiology, School of Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Young-Ho Jin & Sojin Kim

  6. KGC Lifengin, Seoul, 135-549, Republic of Korea

    Jinkyoung Kim

  7. Seoul Sleep Center, Seoul, 135-815, Republic of Korea

    Jin-Kyu Han

  8. Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan

    Makoto Shimizu

  9. State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Zhi-Li Huang

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  1. Suengmok Cho
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  2. Minseok Yoon
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  3. Ae Nim Pae
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  4. Young-Ho Jin
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  5. Nam-Chul Cho
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  8. Sojin Kim
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  9. Jin-Soo Kim
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  11. Jiyoung Kim
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  13. Jin-Kyu Han
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  14. Makoto Shimizu
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  15. Zhi-Li Huang
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Corresponding authors

Correspondence to Makoto Shimizu or Zhi-Li Huang.

Additional information

Suengmok Cho, Minseok Yoon, Makoto Shimizu and Zhi-Li Huang contributed equally to this work.

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Cho, S., Yoon, M., Pae, A.N. et al. Marine polyphenol phlorotannins promote non-rapid eye movement sleep in mice via the benzodiazepine site of the GABAA receptor. Psychopharmacology 231, 2825–2837 (2014). https://doi.org/10.1007/s00213-014-3445-1

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