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β-Eudesmol Induces Neurite Outgrowth in Rat Pheochromocytoma Cells Accompanied by an Activation of Mitogen-Activated Protein Kinase

2002; American Society for Pharmacology and Experimental Therapeutics; Volume: 301; Issue: 3 Linguagem: Inglês

10.1124/jpet.301.3.803

1521-0103

Yutaro Obara, Takashi Aoki, Masayoshi Kusano, Yasushi Ohizumi,

Natural product bioactivities and synthesis

β-Eudesmol, a sesquiterpenoid isolated from "So-jutsu" ( Atractylodis lanceae rhizomas), is known to have various unique effects on the nervous system. We examined in detail the mechanism by which β-eudesmol modified neuronal function using rat pheochromocytoma cells (PC-12). β-Eudesmol at concentrations of 100 and 150 μM significantly induced neurite extension in PC-12 cells, which was accompanied, at the highest concentration, by suppression of [ 3 H]thymidine incorporation. β-Eudesmol at concentrations of 100 and 150 μM also evoked a significant increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) in these cells, as determined by the fura 2 assay. Much of this increase remained even after the extracellular Ca 2+ was chelated by EGTA. The [Ca 2+ ] i increase induced by β-eudesmol was partially inhibited by the phosphoinositide-specific phospholipase C (PI-PLC) inhibitor 1-[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1 H -pyrrole-2,5-dione (U-73122) (2 μM) under extracellular Ca 2+ -free conditions. Furthermore, β-eudesmol, in a concentration-dependent fashion, caused an accumulation of inositol phosphates. β-Eudesmol (150 μM) promoted phosphorylation of both mitogen-activated protein kinase (MAPK) and cAMP-responsive element binding protein in a time-dependent manner. These phosphorylations were suppressed by the MAPK kinase inhibitor 2-(2′-amino-3′-methoxyphenol)-oxanaphthalen-4-one (PD98059) (50 μM), U-73122 (2 μM), the calmodulin inhibitor N -(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W7) (1–10 μM), and the protein kinase A inhibitor N -[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89) (1–10 μM). β-Eudesmol-induced neurite extension was significantly inhibited by both U-73122 (2 μM) and PD98059 (30 μM), suggesting the involvement of PI-PLC and MAPK in neurite outgrowth. β-Eudesmol, being a small molecule, may therefore be a promising lead compound for potentiating neuronal function. Furthermore, the drug may be useful in helping to clarify the mechanisms underlying neuronal differentiation.