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 embryonic striatal and basal forebrain cultures in a concentration-dependent manner. A two- to threefold increase in survival was observed at 75 nM K-252a in both systems. A single application of K-252a at culture initiation prevented substantial (> 60%) cell death that otherwise occurred after 4 days in striatal or basal forebrain cultures. A 5-h exposure of striatal or basal forebrain cells to K-252a, followed by its removal, resulted in survival equivalent to that observed in cultures continually maintained in its presence. This is in contrast to results found with a 5-h exposure of basal forebrain cultures to nerve growth factor (NGF). Acute exposure of basal forebrain cultures to K-252a, but not to NGF, increased ChAT activity, indicating that NGF was required the entire culture period for maximum activity. Striatal cholinergic and GABAergic neurons were among the neurons rescued by K-252a. Of the protein growth factors tested in striatal cultures (ciliary neurotrophic factor, neurotrophin-3, NGF, brain-derived neurotrophic factor, interleukin-2, basic fibroblast growth factor), only brain-derived neurotrophic factor promoted survival. The enhancement of survival and ChAT activity of basal forebrain and striatal neurons by K-252a defines additional populations of neurons in which survival and/or differentiation is regulated by a K-252a-responsive mechanism. The above results expand the potential therapeutic targets for these molecules for the treatment of neuro-degenerative diseases.
Glicksman
M A
MA
Cephalon, Inc., West Chester, Pennsylvania 19380.
Forbes
M E
ME
Prantner
J E
JE
Neff
N T
NT
D000818:Animals; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000201:enzymology*; D026121:Indole Alkaloids; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D010275:Parasympathetic Nervous System / Q000166:cytology; D016548:Prosencephalon / Q000166:cytology / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D002227:Carbazoles; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D005680:gamma-Aminobutyric Acid; C049985:staurosporine aglycone; D002795:Choline O-Acetyltransferase; D011493:Protein Kinase C