Abstract
We have found that honokiol [4-allyl-2-(3-allyl-4-hydroxy-phenyl)-phenol] can promote neurite outgrowth and mobilize intracellular Ca2+ store in primary cultured rat cortical neurons. In this study, we examined the effects of honokiol on extracellular signal-regulated kinases (ERK1/2) and Akt, and their possible relationship to neurite outgrowth and Ca2+ mobilization. Honokiol-induced neurite outgrowth in the cultured rat cortical neurons was significantly reduced by PD98059, a mitogen-activated protein kinase kinase (MAPKK, MAPK/ERK kinase MEK, direct upstream of ERK1/2) inhibitor, but not by LY294002, a phosphoinositide 3-kinase (PI3K, upstream of Akt) inhibitor. Honokiol also significantly enhanced the phosphorylation of ERK1/2 in a concentration-dependent manner, whereas the effect of honokiol on Akt phosphorylation was characterized by transient enhancement in 10 min and lasting inhibition after 30 min. The phosphorylation of ERK1/2 enhanced by honokiol was inhibited by PD98059 as well as by KN93, a Ca2+/calmodulin-dependent kinase II (CaMK II) inhibitor. Moreover, the products of the phosphoinositide specific phospholipase C (PLC)-derived inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG) were measured after honokiol treatment. Together with our previous findings, these results suggest that the signal transduction from PLC, IP3, Ca2+, and CaMK II to ERK1/2 is involved in honokiol-induced neurite outgrowth.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzylamines / pharmacology
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Biphenyl Compounds / pharmacology*
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Blotting, Western
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cells, Cultured
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Cerebral Cortex
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Chromones / pharmacology
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Diglycerides / biosynthesis
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Dose-Response Relationship, Drug
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Drugs, Chinese Herbal / pharmacology
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Enzyme Activation / drug effects
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Female
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Fetus
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Flavonoids / pharmacology
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Inositol 1,4,5-Trisphosphate / biosynthesis
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Lignans / pharmacology*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Models, Biological
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Morpholines / pharmacology
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Neurites / drug effects*
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Neurites / physiology
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Pregnancy
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Protein Kinase Inhibitors / pharmacology
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Rats
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Rats, Sprague-Dawley
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Sulfonamides / pharmacology
Substances
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1,2-diacylglycerol
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Benzylamines
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Biphenyl Compounds
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Chromones
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Diglycerides
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Drugs, Chinese Herbal
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Flavonoids
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Lignans
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Sulfonamides
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honokiol
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KN 93
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Inositol 1,4,5-Trisphosphate
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one