Regulation of glial-derived dopaminergic growth factors by glucocorticoids and protein kinase C

Abstract

Mesencephalic glia secrete factors that support the survival and differentiation of cultured dopaminergic neurons. Crucial to the understanding of the role of glial-derived growth factors in normal and pathophysiological conditions is knowledge about the physiological regulation of their synthesis and secretion. To address this issue, several substances have been tested for effects on the secretion of dopaminergic growth factors from the mesencephalic glial cell line, Mes42. Regulatory influences were assessed by comparing the effects of conditioned medium (CM) obtained from pretreated and untreated Mes42 cells on the survival of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in serum-free low density cultures of the dissociated Embryonic Day 15 rat mesencephalon. This screening demonstrated that corticosterone and dexamethasone decreased the neurotrophic activity of Mes42-CM on TH-IR neurons by 40-60% in a dose-dependent manner. In contrast, the neurotrophic activity of Mes42-CM on TH-IR neurons was enhanced with tetradecanoylphorbol acetate (TPA). Moreover, regulatory effects of glucocorticoids and TPA on secretion of dopaminergic growth factors were not restricted to mesencephalic glial cell lines but also were present in primary mesencephalic glia. Pretreatment of Mes42 cells with 17 beta-estradiol, testosterone, progesterone, basic fibroblast growth factor, transforming growth factor alpha, insulin-like growth factor-I, or activation of cAMP-dependent protein kinases was without effect on the survival promoting activity of Mes42-CM on dopaminergic neurons. These findings suggest that the secretion of dopaminergic growth factors from mesencephalic glia is regulated by glucocorticoids and protein kinase C-dependent second messenger systems.