Induction mechanism of nerve growth factor synthesis by Kami-untan-to; Role of cyclic AMP and c-fos mRNA accumulation.

Kami-untan-to, a Japanese traditional herbal medicine, induces NGF secretion/synthesis on astroglial cells. However, the intracellular signal transduction and genetic mechanisms associated with KUT action have not been clarified. In this paper, the effects of various protein kinase inhibitors on KUT induced NGF secretion of astroglial cells were examined. Pretreatment of astroglial cells with either K-252a, a nonselective protein kinase inhibitor, or H-89, a selective protein kinase A (PKA) inhibitor blocked the KUT-induced NGF secretion in a dose-dependent manner. Treatment of astroglial cells with KUT or forskolin, an adenylate cyclase activator, led to immediate induction of intracellular cyclic AMP (cAMP). Addition of KUT in astroglial cell cultures also induced expression of c-fos mRNA, and was followed by induction of NGF mRNA. Furthermore, pretreatment with c-fos antisense oligonucleotides significantly inhibited the KUT-induced NGF secretion in astroglial cells. These findings suggest that the activation of cAMP-PKA pathway and the induction of c-fos mRNA may play important roles for an enhancing effect of KUT on NGF secretion in astroglial cells.