K-252b is a selective and nontoxic inhibitor of nerve growth factor action on cultured brain neurons.
K-252b is a kinase inhibitor structurally related to K-252a, which is known to abolish selectively the effects of nerve growth factor (NGF) on PC12 cells and PNS neurons. We tested whether K-252b, K-252a, and staurosporine, another related compound, are effective and selective inhibitors of NGF actions on CNS neurons. All three compounds, at appropriate concentrations, completely and selectively prevented the NGF-mediated activity increase of the cholinergic marker enzyme choline acetyltransferase in cultures of rat basal forebrain cells. The stimulatory effects of basic fibroblast growth factor and insulin on choline acetyltransferase in these cultures and on dopamine uptake in cultures of dissociated ventral mesencephalon were not affected. No signs of toxicity were observed in cultures treated with K-252b. In contrast, K-252a and staurosporine, at concentrations required to block the NGF actions on cholinergic cells, were cytotoxic and produced cell loss. In addition, K-252a, at higher concentrations and in the absence of growth factors, increased cell numbers. Our study suggests that K-252b is a selective and nontoxic inhibitor of NGF actions in the brain and may become a useful tool to study these actions in vivo.
Knüsel
B
B
Andrus Gerontology Center, University of Southern California, Los Angeles 90089.
Hefti
F
F
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000196:embryology / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004298:Dopamine / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D026121:Indole Alkaloids; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D019311:Staurosporine
D000470:Alkaloids; D002227:Carbazoles; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; C049985:staurosporine aglycone; D002795:Choline O-Acetyltransferase; D011493:Protein Kinase C; D019311:Staurosporine; D004298:Dopamine