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Prevention of neuronal apoptosis by phorbol ester-induced activation of protein kinase C: blockade of p38 mitogen-activated protein kinase.

Behrens, MM; Strasser, U; Koh, JY; Gwag, BJ; Choi, DW
Neuroscience, 94(3):917-927, 1999
Journal Title
Consistent with previous studies on cell lines and non-neuronal cells, specific inhibitors of protein kinase C induced mouse primary cultured neocortical neurons to undergo apoptosis. To examine the complementary hypothesis that activating protein kinase C would attenuate neuronal apoptosis, the cultures were exposed for 1 h to phorbol-12-myristate-13-acetate, which activated protein kinase C as evidenced by downstream enhancement of the mitogen-activated protein kinase pathway. Exposure to phorbol-12-myristate-13-acetate, or another active phorbol ester, phorbol-12,13-didecanoate, but not to the inactive ester, 4alpha-phorbol-12,13-didecanoate, markedly attenuated neuronal apoptosis induced by serum deprivation. Phorbol-12-myristate-13-acetate also attenuated neuronal apoptosis induced by exposure to beta-amyloid peptide 1-42, or oxygen-glucose deprivation in the presence of glutamate receptor antagonists. The neuroprotective effects of phorbol-12-myristate-13-acetate were blocked by brief (non-toxic) concurrent exposure to the specific protein kinase C inhibitors, but not by a specific mitogen-activated protein kinase 1 inhibitor. Phorbol-12-myristate-13-acetate blocked the induction of p38 mitogen-activated protein kinase activity and specific inhibition of this kinase by SB 203580 attenuated serum deprivation-induced apoptosis. c-Jun N-terminal kinase 1 activity was high at rest and not modified by phorbol-12-myristate-13-acetate treatment. These data strengthen the idea that protein kinase C is a key modulator of several forms of central neuronal apoptosis, in part acting through inhibition of p38 mitogen-activated protein kinase regulated pathways.
MeSH terms
Amyloid beta-Peptides/pharmacologyAnimalsBrain-Derived Neurotrophic Factor/pharmacologyCell HypoxiaCells, CulturedCerebral Cortex/cytology*Coculture TechniquesCulture Media, Serum-FreeCycloheximide/pharmacologyEnzyme Inhibitors/pharmacologyFlavonoids/pharmacologyImidazoles/pharmacologyIndoles/pharmacologyJNK Mitogen-Activated Protein KinasesKineticsMaleimides/pharmacologyMiceMitogen-Activated Protein Kinase 1/metabolismMitogen-Activated Protein Kinases/antagonists & inhibitors*Neurons/cytology*Neurons/drug effectsNeurons/physiology*Peptide Fragments/pharmacologyPhorbol Esters/pharmacology*Protein Kinase C/metabolism*Pyridines/pharmacologyStaurosporine/pharmacologyTetradecanoylphorbol Acetate/pharmacology*p38 Mitogen-Activated Protein Kinases
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Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
곽, 병주
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