REGULATION OF GLIAL-DERIVED DOPAMINERGIC GROWTH-FACTORS BY GLUCOCORTICOIDS AND PROTEIN-KINASE-C

Mesencephalic glia secrete factors that support the survival and diffe rentiation of cultured dopaminergic neurons. Crucial to the understand ing of the role of glial-derived growth factors in normal and pathophy siological conditions is knowledge about the physiological regulation of their synthesis and secretion. To address this issue, several subst ances have been tested for effects on the secretion of dopaminergic gr owth factors from the mesencephalic glial cell line, Mes42. Regulatory influences were assessed by comparing the effects of conditioned medi um (CM) obtained from pretreated and untreated Mes42 cells on the surv ival of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in serum-f ree low density cultures of the dissociated Embryonic Day 15 rat mesen cephalon. This screening demonstrated that corticosterone and dexameth asone decreased the neurotrophic activity of Mes42-CM on TH-IR neurons by 40-60% in a dose-dependent manner. In contrast, the neurotrophic a ctivity of Mes42-CM on TH-IR neurons was enhanced with tetradecanoylph orbol acetate (TPA). Moreover, regulatory effects of glucocorticoids a nd TPA on secretion of dopaminergic growth factors were not restricted to mesencephalic glial cell lines but also were present in primary me sencephalic glia. Pretreatment of Mes42 cells with 17 beta-estradiol, testosterone, progesterone, basic fibroblast growth factor, transformi ng growth factor a, insulin-like growth factor-I, or activation of cAM P-dependent protein kinases was without effect on the survival promoti ng activity of Mes42-CM on dopaminergic neurons. These findings sugges t that the secretion of dopaminergic growth factors from mesencephalic glia is regulated by glucocorticoids and protein kinase C-dependent s econd messenger systems. (C) 1995 Academic Press,Inc.