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

Consistent with previous studies on cell lines and non-neuronal cells, spec ific inhibitors of protein kinase C induced mouse primary cultured neocorti cal neurons to undergo apoptosis. To examine the complementary hypothesis t hat activating protein kinase C would attenuate neuronal apoptosis, the cul tures were exposed for Ih to phorbol-12-myristare-13-acetate, which activat ed protein kinase C as evidenced by downstream enhancement of the mitogen-a ctivated protein kinase pathway. Exposure to phorbol-12-myristate-13-acetat e, or another active phorbol ester, phorbol-12,13-didecanoate, but not to t he inactive ester, 4 alpha-phorbol-12,13-didecanoate, markedly attenuated n euronal apoptosis induced by serum deprivation. Phorbol-12-myristate-13-ace tate also attenuated neuronal apoptosis induced by exposure to beta-amyloid peptide 1-42, or oxygen-glucose deprivation in the presence of glutamate r eceptor 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 I inhibi tor. Phorbol-12-myristate-13-acetate blocked the induction of p38 mitogen-a ctivated protein kinase activity and specific inhibition of this kinase by SE 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 regulate d pathways. (C) 1999 IBRO. Published by Elsevier Science Ltd.