4′-demethylnobiletin, a bioactive metabolite of nobiletin enhancing PKA/ERK/CREB signaling, rescues learning impairment associated with NMDA receptor antagonism via stimulation of the ERK cascade

Md Al Rahim, Akira Nakajima, Daisuke Saigusa, Naomi Tetsu, Yuji Maruyama, Masatoshi Shibuya, Hiroyuki Yamakoshi, Yoshihisa Tomioka, Yoshiharu Iwabuchi, Yasushi Ohizumi, Tohru Yamakuni

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

The biochemical and pharmacological activities of nobiletin, including neurotrophic and memory-enhancing action, in both in vitro and in vivo systems are well established. However, whether its metabolites do have such beneficial effects like nobiletin remains to be examined. Here we, for the first time, report that 2-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one (4′-demethylnobiletin), a major metabolite of nobiletin identified in the urine of rats and mice, stimulates the phosphorylation of ERK and CREB and enhances CRE-mediated transcription by activating a PKA/MEK/ERK pathway, like nobiletin, in cultured hippocampal neurons. Since NMDA receptor-mediated ERK signaling is involved in memory processing, including associative memories, we also examined whether 4′-demethylnobiletin, by activating ERK signaling, could restore learning impairment. Chronic intraperitoneal (ip) treatment of the mice with 10 or 50 mg of 4′-demethylnobiletin/kg rescued the NMDA receptor antagonist MK-801-induced learning impairment, accompanied by improvement of the MK-801-induced decrease in the level of ERK phosphorylation in the hippocampus of the animals. Consistently, 4′-demethylnobiletin also restored MK-801-induced inhibition of NMDA-stimulated phosphorylation of not only ERK but also PKA substrates in cultured rat hippocampal neurons. Moreover, we actually detected 4′-demethylnobiletin in the brain of mice following acute ip administration, demonstrating that the metabolite can cross the blood-brain barrier to reach the brain and thereby exert its effects to reverse learning impairment. Therefore, these results suggest that 4′- demethylnobiletin, a bioactive metabolite of nobiletin, may serve as a potential therapeutic agent, at least, for memory disorders associated with a dysregulated NMDA receptor ERK signaling, like nobiletin.

Original languageEnglish
Pages (from-to)7713-7721
Number of pages9
JournalBiochemistry
Volume48
Issue number32
DOIs
Publication statusPublished - 2009 Aug 18

ASJC Scopus subject areas

  • Biochemistry

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