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

Ichiro Kawahata, Masaaki Yoshida, Wen Sun, Akira Nakajima, Yanxin Lai, Naoya Osaka, Kentaro Matsuzaki, Akihito Yokosuka, Yoshihiro Mimaki, Akira Naganuma, Yoshihisa Tomioka, Tohru Yamakuni

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1397-1409
Number of pages13
JournalJournal of Neural Transmission
Volume120
Issue number10
DOIs
Publication statusPublished - 2013 Oct

Keywords

  • CRE-mediated transcription
  • Hippocampal neurons
  • Learning and memory
  • Nobiletin-rich Citrus reticulata peel
  • PKA/ERK/CREB signaling

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this