title: Prevention of neuronal apoptosis by phorbol ester-induced activation of protein kinase C: blockade of p38 mitogen-activated protein kinase.
abstract: 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.
authors.affiliation: Department of Neurology and Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA. behrensm@neuro.wustl.edu
authors.forename: M M
authors.initials: MM
authors.lastname: Behrens
authors.forename: U
authors.initials: U
authors.lastname: Strasser
authors.forename: J Y
authors.initials: JY
authors.lastname: Koh
authors.forename: B J
authors.initials: BJ
authors.lastname: Gwag
authors.forename: D W
authors.initials: DW
authors.lastname: Choi
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D010446:Peptide Fragments; D010703:Phorbol Esters; D011725:Pyridines; C075222:amyloid beta-protein (1-42); C008876:phorbol-12,13-didecanoate; D003513:Cycloheximide; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019311:Staurosporine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one