Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells
Identifieur interne : 001683 ( Main/Exploration ); précédent : 001682; suivant : 001684Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells
Auteurs : Hui-Chi Lai [Taïwan] ; Ming-Jiuan Wu [Taïwan] ; Pei-Yi Chen [Taïwan] ; Ting-Ting Sheu [Taïwan] ; Szu-Ping Chiu [Taïwan] ; Meng-Han Lin [Taïwan] ; Chi-Tang Ho [États-Unis] ; Jui-Hung Yen [Taïwan]Source :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-OH-HxMF), a hydroxylated polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. In this research, we report the first investigation of the neurotrophic effects and mechanism of 5-OH-HxMF in PC12 pheochromocytoma cells. We found that 5-OH-HxMF can effectively induce PC12 neurite outgrowth accompanied with the expression of neuronal differentiation marker protein growth-associated protein-43(GAP-43). 5-OH-HxMF caused the enhancement of cyclic AMP response element binding protein (CREB) phosphorylation, c-fos gene expression and CRE-mediated transcription, which was inhibited by 2-naphthol AS-E phosphate (KG-501), a specific antagonist for the CREB-CBP complex formation. Moreover, 5-OH-HxMF-induced both CRE transcription activity and neurite outgrowth were inhibited by adenylate cyclase and protein kinase A (PKA) inhibitor, but not MEK1/2, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K) or calcium/calmodulin-dependent protein kinase (CaMK) inhibitor. Consistently, 5-OH-HxMF treatment increased the intracellular cAMP level and downstream component, PKA activity. We also found that addition of K252a, a TrKA antagonist, significantly inhibited NGF- but not 5-OH-HxMF-induced neurite outgrowth. These results reveal for the first time that 5-OH-HxMF is an effective neurotrophic agent and its effect is mainly through a cAMP/PKA-dependent, but TrKA-independent, signaling pathway coupling with CRE-mediated gene transcription. A PKC-dependent and CREB-independent pathway was also involved in its neurotrophic action.
Url:
DOI: 10.1371/journal.pone.0028280
PubMed: 22140566
PubMed Central: 3226691
Affiliations:
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Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Pei Yi" sort="Chen, Pei Yi" uniqKey="Chen P" first="Pei-Yi" last="Chen">Pei-Yi Chen</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institute of Medical Science, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Medical Science, Tzu Chi University, Hualien</wicri:regionArea><wicri:noRegion>Hualien</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Center of Medical 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Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Medical Science, Tzu Chi University, Hualien</wicri:regionArea><wicri:noRegion>Hualien</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-OH-HxMF), a hydroxylated polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. In this research, we report the first investigation of the neurotrophic effects and mechanism of 5-OH-HxMF in PC12 pheochromocytoma cells. We found that 5-OH-HxMF can effectively induce PC12 neurite outgrowth accompanied with the expression of neuronal differentiation marker protein growth-associated protein-43(GAP-43). 5-OH-HxMF caused the enhancement of cyclic AMP response element binding protein (CREB) phosphorylation, c-fos gene expression and CRE-mediated transcription, which was inhibited by 2-naphthol AS-E phosphate (KG-501), a specific antagonist for the CREB-CBP complex formation. Moreover, 5-OH-HxMF-induced both CRE transcription activity and neurite outgrowth were inhibited by adenylate cyclase and protein kinase A (PKA) inhibitor, but not MEK1/2, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K) or calcium/calmodulin-dependent protein kinase (CaMK) inhibitor. Consistently, 5-OH-HxMF treatment increased the intracellular cAMP level and downstream component, PKA activity. We also found that addition of K252a, a TrKA antagonist, significantly inhibited NGF- but not 5-OH-HxMF-induced neurite outgrowth. These results reveal for the first time that 5-OH-HxMF is an effective neurotrophic agent and its effect is mainly through a cAMP/PKA-dependent, but TrKA-independent, signaling pathway coupling with CRE-mediated gene transcription. A PKC-dependent and CREB-independent pathway was also involved in its neurotrophic action.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bui, Nt" uniqKey="Bui N">NT Bui</name></author><author><name sortKey="Konig, Hg" uniqKey="Konig H">HG Konig</name></author><author><name sortKey="Culmsee, C" uniqKey="Culmsee C">C Culmsee</name></author><author><name sortKey="Bauerbach, E" uniqKey="Bauerbach E">E Bauerbach</name></author><author><name sortKey="Poppe, M" uniqKey="Poppe M">M Poppe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schulte Herbruggen, O" uniqKey="Schulte Herbruggen O">O Schulte-Herbruggen</name></author><author><name sortKey="Jockers Scherubl, Mc" uniqKey="Jockers Scherubl M">MC Jockers-Scherubl</name></author><author><name sortKey="Hellweg, R" uniqKey="Hellweg R">R Hellweg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Levy, Ys" uniqKey="Levy 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