Regulation of Nerve Growth Factor (NGF) Synthesis in the Rat Central Nervous System: Comparison between the Effects of Interleukin-1 and Various Growth Factors in Astrocyte Cultures and in vivo.

Abstract

In order to obtain information on the physiological regulation of NGF-synthesis in the central nervous system (CNS) we investigated the effects of a series of growth factors (known to be present in the CNS) in cultures of purified rat astrocytes and compared these effects with those observed after intraventricular injection of the same molecules. After preliminary experiments had shown that 10% fetal calf serum (FCS) produced a marked increase in NGF-mRNA levels in astrocytes (but neither in microglia nor oligodendrocytes) as demonstrated by Northern blot analysis and in situ hybridization the experiments were performed at low (0.5%) FCS concentrations. Supramaximal concentrations of IL-1 and various growth factors caused a 5- to 7-fold increase in NGF-mRNA after 6 h. By 24 h the NGF-mRNA levels approached control values again, most probably due to inactivation of the added factors since after readdition after 24 h the response was about the same as the initial one. Norepinephrine and 8-bromo-cAMP did not change NGF-mRNA levels. The growth factor-mediated changes in NGF-mRNA levels in astrocyte cultures were not consistently reflected by the changes observed after intraventricular injection. IL-1 produced by far the largest increase in hippocampal NGF-mRNA after intraventricular injection. This large response to IL-1 could result from a positive feedback mechanism, since IL-1beta injection not only increases NGF-mRNA but also IL-1beta-mRNA in the hippocampus. The understanding of the physiological regulation of NGF synthesis in the CNS is the basis for a rational approach to its pharmacological modification. This, in turn, is an attractive alternative to the (long-term) infusion of NGF or the transplantation of NGF-secreting cells with the goal of providing trophic support to the cholinergic neurons of the basal forebrain nuclei. These neurons are consistently affected in the early stages of Alzheimer's disease, their impaired function being essentially responsible for the cognitive deficits.