CYCLIC-AMP-DEPENDENT REGULATION OF FIBROBLAST GROWTH FACTOR-II MESSENGER-RNA LEVELS IN RAT CORTICAL ASTROCYTES - COMPARISON WITH FIBROBLASTGROWTH-FACTOR-I AND CILIARY NEUROTROPHIC FACTOR

The present study was undertaken to investigate the regulatory mechani sms of fibroblast growth factor-1 and -2 (FGF-1 and FGF-2) gene expres sion compared with ciliary neurotrophic factor (CNTF) in rat cortical astrocytes. Glial cells represent a source of different trophic factor s and cytokines that can influence the survival of multiple cell popul ations within the central nervous system. We found that the beta-adren ergic receptor ag onist (beta AR) 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 re duced after exposure to isoproterenol. The changes produced by the bet a AR agonist is mimicked by cyclic AMP analogues (8-bromo-cAMP) or 3-i sobutyl-1-methyl-xanthine, a cAMP phosphodiesterase inhibitor, which i ndicates that intracellular elevation of this second messenger is resp onsible for these effects. The regulation of neurotrophic factors by i soproterenol is not restricted to cortical astrocytes and may take pla ce through different mechanisms. Inhibition of protein synthesis preve nts the decrease in CNTF without affecting the changes in FGF-1 and FG F-2 gene expression. Coincubation of isoproterenol with actinomycin D, an inhibitor of gene transcription, prevents the modification of neur otrophic factor biosynthesis, indicating that transcriptional mechanis ms are indeed involved in these regulatory pathways. However, the dete rmination of FGF-2 mRNA half-life suggests that the effect of the PAR agonist can be in part the result of mRNA stabilization. The mechanism s that we describe can be important in the maintenance of neuronal hom eostasis and may be relevant in the development of alternative strateg ies for the treatment of acute and chronic neurodegenerative disorders .