K-252A PROMOTES SURVIVAL AND CHOLINE-ACETYLTRANSFERASE ACTIVITY IN STRIATAL AND BASAL FOREBRAIN NEURONAL CULTURES

The organic molecule K-252a promoted cell survival, neurite outgrowth, and increased choline acetyltransferase (ChAT) activity in rat embryo nic striatal and basal forebrain cultures in a concentration-dependent manner. A two- to threefold increase in survival was observed at 75 n M K-252a in both systems. A single application of K-252a at culture in itiation prevented substantial (>60%) cell death that otherwise occurr ed after 4 days in striatal or basal forebrain cultures. A 5-h exposur e of striatal or basal forebrain cells to K-252a, followed by its remo val, resulted in survival equivalent to that observed in cultures cont inually maintained in its presence. This is in contrast to results fou nd with a 5-h exposure of basal forebrain cultures to nerve growth fac tor (NGF). Acute exposure of basal forebrain cultures to K-252a, but n ot to NGF, increased ChAT activity, indicating that NGF was required t he entire culture period for maximum activity. Striatal cholinergic an d GABAergic neurons were among the neurons rescued by K-252a. Of the p rotein growth factors tested in striatal cultures (ciliary neurotrophi c factor, neurotrophin-3, NGF, brain-derived neurotrophic factor, inte rleukin-2, basic fibroblast growth factor), only brain-derived neurotr ophic factor promoted survival. The enhancement of survival and ChAT a ctivity of basal forebrain and striatal neurons by K-252a defines addi tional populations of neurons in which survival and/or differentiation is regulated by a K-252a-responsive mechanism. The above results expa nd the potential therapeutic targets for these molecules for the treat ment of neurodegenerative diseases.