Since
neurotrophic factors are essential for neurons to form neuronal networks and maintain neuronal functions,
neurotrophic factor-like substances or inducers of
neurotrophic factors can be useful for the treatment of serious neuronal diseases such as Alzheimer's and Parkinson's diseases. In the present study, we examined an effect of
5,19-cyclo-9beta,10xi-androstane-3,17-dione (CAD) on
neurotrophic factor synthesis in glial cells and
scopolamine-induced impairment of learning in mice. 1321N1 human
astrocytoma cells promoted secretion of certain
neurotrophic factors in response to CAD with no cytotoxicity, which caused dramatic neurite outgrowth in rat
pheochromocytoma (PC12) cells. In fact, CAD significantly enhanced
nerve growth factor (
NGF) secretion and its gene expression in 1321N1 cells, in a time and concentration-dependent manner. Because second messengers such as cAMP,
inositol 1,4,5-trisphosphates and Ca(2+) induce
NGF gene expression, we measured activities of
adenylyl cyclase and
phospholipase C and intracellular Ca(2+) concentration in 1321N1 cells. However, CAD changed neither second messenger levels. CAD enhanced the gene expression of proto-oncogene, c-fos that is one of the components of
transcription factor (AP-1). In addition to those above, the in vivo effects of CAD were also examined. Although injection of
muscarinic receptor antagonist
scopolamine impaired passive avoidance learning in mice, pretreatment with CAD significantly reversed the adverse effect in a dose-dependent manner. Taking these results together, CAD has enormous therapeutic potential for serious neuronal diseases.