Polymethoxyflavones (PMFs) are the major flavonoids found in the peer of citrus fruits and have been reported to exhibit several biological activities. In the present study, we focused on the effects and mechanisms of the citrus 5-hydroxylated PMF, 5-hydroxy-6,7,8,3',4'- pentamethoxyflavone (HPF), and a synthetic analogue, Gardenin A (GA), on promoting neuritogenesis in PC12 cells. We found that HPF and GA significantly induced neurite outgrowth in PC12 cells. We further analyzed the molecular signaling pathways involved in the HPF- and GA-induced neurite outgrowth by using pharmacological inhibitors. Our data showed that both HPF- and GA-induced neuritogenesis of PC12 cells were significantly reduced with inhibitors KG-501 (p-CREB), U0126 (MEK1/2), bisindolylmaleimide I (PKC) and H-89 (PKA), respectively. Our results also demonstrated HPF and GA increased the levels of p-CREB and the cAMP response element (CRE)-driven transcription in PC12 cells. The compound-mediated CREB activation significantly inhibited by MEK1/2, PKA and PKC inhibitors. These above findings reveal that HPF and GA promoted neurite outgrowth through ERK-, PKC- and PKA-dependent CREB activation, which may contribute to CRE-mediated gene expression for promoting the neuritogenic action in PC12 cells.

Citrus 5-hydroxylated polymethoxyflavones promote neuritogenesis through cAMP response element binding protein (CREB) pathway in PC12 cells

243rd National Meeting (2012)

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