title: Inhibition of nerve growth factor-induced neurite outgrowth from PC12 cells by dexamethasone: signaling pathways through the glucocorticoid receptor and phosphorylated Akt and ERK1/2.
abstract: Glucocorticoids are important mediators of the stress response and are commonly employed as drugs for the suppression of immune rejection after organ transplantation. Previous investigations uncovered the possibility of mood depression in patients undergoing long-term treatment with synthetic glucocorticoids, including dexamethasone (DEX). Exogenous glucocorticoids and their synthetic derivatives can also adversely affect the development of the central nervous system. Although neurite extension from rat pheochromocytoma-derived PC12 cells and a variety of primary neurons is stimulated by nerve growth factor (NGF), and signaling pathways triggered by the binding of NGF to tyrosine kinase receptor type 1 (TrkA) function in both neurite outgrowth and neuronal survival, the effect of DEX on the activation of regulatory proteins and pathways downstream of TrkA has not been well characterized. To analyze the influence of DEX on NGF-induced neurite outgrowth and signaling, PC12 cells, a widely utilized model of neuronal differentiation, were pretreated with the glucocorticoid prior to NGF induction. NGF-induced neurite outgrowth was attenuated by pretreatment with DEX, even in the absence of DEX after the addition of NGF. Moreover, DEX suppressed the phosphorylation of Akt and extracellular-regulated kinase 1/2 (ERK1/2) in the neurite outgrowth signaling cascade initiated by NGF. Finally, the glucocorticoid receptor (GR) antagonist, RU38486, counteracted the inhibitory effect of DEX pretreatment, not only on the phosphorylation of Akt and ERK1/2, but also on neurite extension from PC12 cells. These results suggest that DEX binding to the GR impairs NGF-promoted neurite outgrowth by interfering with the activation/phosphorylation of Akt and ERK1/2. These novel findings are likely to be useful for elucidating the central nervous system depressive mechanism(s) of action of DEX and other glucocorticoids.
authors.affiliation: Laboratory of Drug Design and Drug Delivery, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; Laboratory of Clinical Pharmacology, Yokohama College of Pharmacy, Kanagawa, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Terada
authors.affiliation: Research and Development Department 2, Nippon Sigmax Co., Ltd., Tokyo, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Research and Development Department 2, Nippon Sigmax Co., Ltd., Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Laboratory of Clinical Pharmacology, Yokohama College of Pharmacy, Kanagawa, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Izumo
authors.affiliation: Laboratory of Clinical Pharmacology, Yokohama College of Pharmacy, Kanagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Drug Design and Drug Delivery, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Karube
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D015735:Mifepristone / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D020932:Nerve Growth Factor; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3