Mechanism of Neurotrophic Action of Nobiletin in PC12D Cells

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• 作者：Hiroyuki Nagase ; Tohru Yamakuni ; Kentaro Matsuzaki ; Yuji Maruyama ; Jiro Kasahara ; Yoshimi Hinohara ; Shunzo Kondo ; Yoshihiro Mimaki ; Yutaka Sashida ; A. William Tank ; Kohji Fukunaga ; and Yasushi Ohizumi
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：October 25, 2005
• 年：2005
• 卷：44
• 期：42
• 页码：13683 - 13691
• 全文大小：607K
• 年卷期：v.44,no.42(October 25, 2005)
• ISSN：1520-4995

文摘

Nobiletin is a nonpeptide compound with a low molecular weight from a citrus fruit and hasthe activity to rescue bulbectomy-induced memory impairment. Here we describe that nobiletin itselfinduces neurite outgrowth in PC12D cells, a rat pheochromocytoma cell line, like NGF, and the molecularmechanism of its neurotrophic action. As cultured in the presence of nobiletin or NGF for 48 h and thenassayed using a scanning electron microscope, PC12D cells treated with nobiletin showed morphologywith flatter and larger cell bodies than the cells cultured with NGF. Nobiletin-induced neurite outgrowthwas 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 phosphorylationof MEK and Erk/MAP kinase, resulting in a stimulation of CREB phosphorylation and CRE-mediatedtranscription. This compound also increased intracellular cAMP and CRE-mediated transcription in thepresence of forskolin and enhanced PKA activity to stimulate phosphorylation of multiple PKA substratesin PC12D cells. Furthermore, nobiletin preferentially inhibited Ca²⁺/CaM-dependent phosphodiesterasein vitro. This compound failed to stimulate phosphorylation of Erk5, which is known to be induced byNGF/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 ofthe molecular mechanism of neuronal differentiation.