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.
Highlights
Glucocorticoids are critical mediators of the stress response in neurons and other cell types
The present study utilized PC12 cells as a neuronal model to demonstrate that nerve growth factor (NGF)-induced neurite outgrowth, a hallmark of neuronal morphological differentiation, was blocked by pretreatment of the cells with a synthetic glucocorticoid, DEX (Fig. 1)
DEX-mediated interference with neurite outgrowth was accompanied by specific neurobiochemical changes, as evidenced by the downregulation of phosphorylated Akt and extracellularregulated kinase 1/2 (ERK1/2) levels in the NGF-treated cultures (Fig. 2)
Summary
Glucocorticoids are critical mediators of the stress response in neurons and other cell types. Exposure of cells to stress triggers the glucocorticoid-mediated activation of corticotropin-releasing hormones, which in turn stimulate the synthesis of pituitary corticotropin as a part of the hypothalamo-pituitary adrenal axis [1]. Glucocorticoids are involved in cell proliferation, neurotransmitter synthesis [2], neuronal survival, and neuronal differentiation [3,4]. Synthetic glucocorticoids such as dexamethasone (DEX) are used for the suppression of immune rejection after organ transplantation and in the treatment of leukemia. Prenatal exposure to DEX can lead to the abnormal development of the central nervous system [6,7]
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