Neurotrophic Action of 5-Hydroxylated Polymethoxyflavones: 5-Demethylnobiletin and Gardenin A Stimulate Neuritogenesis in PC12 Cells

作者：Chiu Szu Ping; Wu Ming Jiuan; Chen Pei Yi; Ho Yi Ru; Tai Mi Hsueh; Ho Chi Tang; Yen Jui Hung^*

来源：Journal of Agricultural and Food Chemistry, 2013, 61(39): 9453-9463.

DOI：10.1021/jf4024678

• polymethoxyflavones
• 5-demethylnobiletin
• gardenin A
• PC12 cells
• neurite outgrowth

Polymethoxyflavones (PMFs) exhibit a broad spectrum of biological properties, including anticancer, antiatherogenic, and neuroprotective effects. The aim of this study is to investigate the neurotrophic effects of 5-demethylnobiletin, a hydroxylated PMF found in citrus plants, and gardenin A, a synthetic PMF analogue, on neurite outgrowth and neuronal differentiation in PC12 cells. The results of this study showed that 5-demethylnobiletin and gardenin A (10-20 mu M) potently induce neurite outgrowth in PC12 cells, accompanied by the expression of neuronal differentiation and synapse formation marker proteins, growth associated protein-43 (GAP-43), and synaptophysin. We observed that the addition of K252a, a TrKA antagonist, significantly inhibited NGF-induced neurite outgrowth in PC12 cells, but 5-demethylnobiletin- or gardenin A-induced neurite outgrowth was not affected. Treatment with 5-demethylnobiletin and gardenin A markedly induced the phosphorylation of both cyclic AMP response element-binding protein (CREB) and CRE-mediated transcription, which was suppressed through the administration of the inhibitor 2-naphthol AS-E phosphate (KG-501) or. using CREB siRNA. Furthermore, our results showed that MAPK/ERK kinase 1/2 (MEK1/2), protein kinase A (PKA), and protein kinase C (PKC) inhibitors blocked the CRE transcription activity and neurite outgrowth induced through 5-demethylnobiletin or gardenin A. Consistently, increased ERK phosphorylation and PKA and PKC activities were observed in PC12 cells treated with 5-demethylnobiletin or gardenin A. These results reveal for the first time that 5-demethylnobiletin and gardenin A promote neuritogenesis through the activation of MAPK/ERK-, PKC-, and PICA dependent, but not TrkA-dependent, CREB signaling pathways in PC12 cells.

• 出版日期2013-10-2
• 单位河北医科大学