Cyclic AMP-dependent regulation of fibroblast growth factor-2 messenger RNA levels in rat cortical astrocytes: comparison with fibroblast growth factor-1 and ciliary neurotrophic factor.

The present study was undertaken to investigate the regulatory mechanisms of fibroblast growth factor-1 and -2 (FGF-1 and FGF-2) gene expression compared with ciliary neurotropic factor (CNTF) in rat cortical astrocytes. Glial cells represent a source of different trophic factors and cytokines that can influence the survival of multiple cell populations within the central nervous system. We found that the beta-adrenergic receptor agonist (betaAR) isoproterenol produced a significant induction of FGF-2 gene expression and protein in type I astrocytes. On the contrary, the gene expression for FGF-1 and CNTF is markedly reduced after exposure to isoproterenol. The changes produced by the beta AR agonist is mimicked by cyclic AMP analogues (8-bromo-cAMP) or 3-isobutyl-1-methyl-xanthine, a cAMP phosphodiesterase inhibitor, which indicates that intracellular elevation of this second messenger is responsible for these effects. The regulation of neurotrophic factors by isoproterenol is not restricted to cortical astrocytes and may take place through different mechanisms. Inhibition of protein synthesis prevents the decrease in CNTF without affecting the changes in FGF-1 and FGF-2 gene expression. Coincubation of isoproterenol with actinomycin D, an inhibitor of gene transcription, prevents the modification of neurotrophic factor biosynthesis, indicating that transcriptional mechanisms are indeed involved in these regulatory pathways. However, the determination of FGF-2 mRNA half-life suggests that the effect of the betaAR agonist can be in part the result of mRNA stabilization. The mechanisms that we describe can be important in the maintenance of neuronal homeostasis and may be relevant in the development of alternative strategies for the treatment of acute and chronic neurodegenerative disorders