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Potent activity of nobiletin-rich Citrus reticulata peel extract to facilitate cAMP/PKA/ERK/CREB signaling associated with learning and memory in cultured hippocampal neurons: identification of the substances responsible for the pharmacological action

  • Translational Neurosciences - Original Article
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Abstract

cAMP/PKA/ERK/CREB signaling linked to CRE-mediated transcription is crucial for learning and memory. We originally found nobiletin as a natural compound that stimulates this intracellular signaling and exhibits anti-dementia action in animals. Citrus reticulata or C.unshiu peels are employed as “chinpi” and include a small amount of nobiletin. We here provide the first evidence for beneficial pharmacological actions on the cAMP/PKA/ERK/CREB cascade of extracts from nobiletin-rich C.reticulata peels designated as Nchinpi, the nobiletin content of which was 0.83 ± 0.13 % of the dry weight or 16-fold higher than that of standard chinpi extracts. Nchinpi extracts potently facilitated CRE-mediated transcription in cultured hippocampal neurons, whereas the standard chinpi extracts showed no such activity. Also, the Nchinpi extract, but not the standard chinpi extract, stimulated PKA/ERK/CREB signaling. Interestingly, treatment with the Nchinpi extract at the concentration corresponding to approximately 5 μM nobiletin more potently facilitated CRE-mediated transcriptional activity than did 30 μM nobiletin alone. Consistently, sinensetin, tangeretin, 6-demethoxynobiletin, and 6-demethoxytangeretin were also identified as bioactive substances in Nchinpi that facilitated the CRE-mediated transcription. Purified sinensetin enhanced the transcription to a greater degree than nobiletin. Furthermore, samples reconstituted with the four purified compounds and nobiletin in the ratio of each constituent’s content in the extract showed activity almost equal to that of the Nchinpi extract to stimulate CRE-mediated transcription. These findings suggest that above four compounds and nobiletin in the Nchinpi extract mainly cooperated to facilitate potently CRE-mediated transcription linked to the upstream cAMP/PKA/ERK/CREB pathway in hippocampal neurons.

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Acknowledgments

We thank Dr. T. Shimizu for identification of the origins of the crude drugs employed for the present study, and Dr. L.D. Frye for English editing of the manuscript.

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Author notes

  1. Akira Nakajima

    Present address: Department of Neuropsychopharmacology and Hospital Pharmacy, School of Medicine, Nagoya University, Tsuruma-cho, Showa-ku, Nagoya, 466-8560, Japan

Authors and Affiliations

  1. Department of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki Aoba-ku, Sendai, 980-8578, Japan

    Ichiro Kawahata, Wen Sun, Akira Nakajima, Yanxin Lai, Naoya Osaka & Tohru Yamakuni

  2. Research Laboratory, Kotaro Pharmaceutical Co., Ltd, Ro 96-1 Kashima-machi, Hakusan, Ishikawa, 920-0201, Japan

    Masaaki Yoshida

  3. Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Shioya, Izumo-shi, Shimane, 693-8501, Japan

    Kentaro Matsuzaki

  4. Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, 192-0392, Japan

    Akihito Yokosuka & Yoshihiro Mimaki

  5. Department of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

    Akira Naganuma

  6. Department of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

    Yoshihisa Tomioka

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  1. Ichiro Kawahata
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  2. Masaaki Yoshida
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  9. Yoshihiro Mimaki
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Corresponding author

Correspondence to Tohru Yamakuni.

Additional information

I. Kawahata and M. Yoshida equally contributed to this work.

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Kawahata, I., Yoshida, M., Sun, W. et al. Potent activity of nobiletin-rich Citrus reticulata peel extract to facilitate cAMP/PKA/ERK/CREB signaling associated with learning and memory in cultured hippocampal neurons: identification of the substances responsible for the pharmacological action. J Neural Transm 120, 1397–1409 (2013). https://doi.org/10.1007/s00702-013-1025-x

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  • DOI: https://doi.org/10.1007/s00702-013-1025-x

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