Mechanism of Neurotrophic Action of Nobiletin in PC12D Cells

Nobiletin is a nonpeptide compound with a low molecular weight from a citrus fruit and has the activity to rescue bulbectomy-induced memory impairment. Here we describe that nobiletin itself induces neurite outgrowth in PC12D cells, a rat pheochromocytoma cell line, like NGF, and the molecular mecha...

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Published in:Biochemistry (Easton) 2005-10, Vol.44 (42), p.13683-13691
Main Authors: Nagase, Hiroyuki, Yamakuni, Tohru, Matsuzaki, Kentaro, Maruyama, Yuji, Kasahara, Jiro, Hinohara, Yoshimi, Kondo, Shunzo, Mimaki, Yoshihiro, Sashida, Yutaka, Tank, A. William, Fukunaga, Kohji, Ohizumi, Yasushi
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Citrus
Cyclic AMP Response Element-Binding Protein - metabolism
Enzyme Activation
Flavones - pharmacology
Hippocampus - cytology
Hippocampus - drug effects
Hippocampus - enzymology
Hippocampus - metabolism
MAP Kinase Signaling System
Microscopy, Electron, Scanning
Neurons - drug effects
Neurons - enzymology
Neurons - metabolism
PC12 Cells
Phosphorylation
Rats
Transcription, Genetic
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Summary:Nobiletin is a nonpeptide compound with a low molecular weight from a citrus fruit and has the activity to rescue bulbectomy-induced memory impairment. Here we describe that nobiletin itself induces neurite outgrowth in PC12D cells, a rat pheochromocytoma cell line, like NGF, and the molecular mechanism of its neurotrophic action. As cultured in the presence of nobiletin or NGF for 48 h and then assayed using a scanning electron microscope, PC12D cells treated with nobiletin showed morphology with flatter and larger cell bodies than the cells cultured with NGF. Nobiletin-induced neurite outgrowth was inhibited by PD98059 and U0126 but not K252a. Consistently, nobiletin caused a concentration-dependent enhancement of Erk/MAP kinase phosphorylation and a sustained increment of phosphorylation of MEK and Erk/MAP kinase, resulting in a stimulation of CREB phosphorylation and CRE-mediated transcription. This compound also increased intracellular cAMP and CRE-mediated transcription in the presence of forskolin and enhanced PKA activity to stimulate phosphorylation of multiple PKA substrates in PC12D cells. Furthermore, nobiletin preferentially inhibited Ca2+/CaM-dependent phosphodiesterase in vitro. This compound failed to stimulate phosphorylation of Erk5, which is known to be induced by NGF/TrkA signaling. These results suggest that nobiletin induces neurite outgrowth by activating a cAMP/PKA/MEK/Erk/MAP kinase-dependent but not TrkA-dependent signaling pathway coupling with CRE-mediated gene transcription and may thus become a novel type of biochemical probe for elucidation of the molecular mechanism of neuronal differentiation.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi050643x