Honokiol-induced neurite outgrowth promotion depends on activation of extracellular signal-regulated kinases (ERK1/2).
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.
Zhai
Haifeng
H
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima 770-8514, Japan.
Nakade
Kousuke
K
Oda
Masataka
M
Mitsumoto
Yasuhide
Y
Akagi
Masaaki
M
Sakurai
Jun
J
Fukuyama
Yoshiyasu
Y
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex; D002867:Chromones / Q000494:pharmacology; D004075:Diglycerides / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005333:Fetus; D005419:Flavonoids / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D017705:Lignans / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D000498:Allyl Compounds; D010636:Phenols; D000096926:Benzenesulfonamides
D001596:Benzylamines; D001713:Biphenyl Compounds; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D004075:Diglycerides; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D015544:Inositol 1,4,5-Trisphosphate; D017705:Lignans; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C011439:1,2-diacylglycerol; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C072105:KN 93; D000096926:Benzenesulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one