Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities

Hiroyuki Nagase, Naoki Omae, Akiko Omori, Osamu Nakagawasai, Takeshi Tadano, Akihito Yokosuka, Yutaka Sashida, Yoshihiro Mimaki, Tohru Yamakuni, Yasushi Ohizumi

Research output: Contribution to journalArticlepeer-review

122 Citations (Scopus)

Abstract

cAMP response element (CRE) transcription is dysregulated in neurodegenerative disorders in the central nervous system (CNS), including polyglutamine diseases. As the first step to find natural compounds with protective action against neurodegeneration in the CNS, we here examined whether six citrus flavonoids, namely nobiletin, 5-demethylnobiletin, tangeretin, sinensetin, 6-demethoxytangeretin, and 6-demethoxynobiletin, stimulated CRE-dependent transcription and induced neurite outgrowth in PC12D cells. Among the compounds, nobiletin most potently enhanced CRE-dependent transcription and neurite outgrowth by activating ERK/MAP kinase-dependent signalling to increase CREB phosphorylation. The transcription and neurite outgrowth were stimulated by nobiletin in a concentration-dependent manner, with a strong correlation between them. Furthermore, a 11-day oral administration of nobiletin rescued impaired memory in olfactory-bulbectomized mice documented to be accompanied by a cholinergic neurodegeneration. These results suggest that nobiletin with the activity to improve impaired memory may become a potential leading compound for drug development for neurodegenerative disorders exhibiting the dysregulated CRE-dependent transcription.

Original languageEnglish
Pages (from-to)1330-1336
Number of pages7
JournalBiochemical and biophysical research communications
Volume337
Issue number4
DOIs
Publication statusPublished - 2005 Dec 2

Keywords

  • Bulbectomy
  • CRE-dependent transcription
  • Flavonoids
  • Memory impairment
  • Neurite outgrowth
  • Neurodegeneration
  • Nobiletin

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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