INHIBITORS OF P38 MITOGEN-ACTIVATED PROTEIN-KINASE PROMOTE NEURONAL SURVIVAL IN-VITRO

Mammalian mitogen-activated protein kinases include the extracellular signal-regulated protein kinase, the c-Jun amino-terminal kinase, and the p38 subgroups. Sustained activation of Jun kinase and p38 have bee n shown to precede apoptosis of PC12 pheochromocytoma cells induced by withdrawal of trophic factors. To investigate the possible role of p3 8 in neuronal apoptosis, we tested the effect of two selective p38 inh ibitors, the pyridinyl imidazole compounds SB203580 and SB202190, on d ifferent populations of chick embryonic neurons in vitro. Both substan ces promoted the in vitro survival of sensory, sympathetic, ciliary an d motor neurons in a dose-dependent fashion. When assayed in nerve gro wth factor-stimulated PC12 cells, SB203580 pretreatment inhibited the activation of both ribosomal S6 kinases-1 and -2 with the same IC50 (a pproximately 30 mu M) that inhibited apoptosis in primary neurons. Thu s, p38 inhibitor-sensitive pathways may be involved in apoptosis of ne urotrophic factor-deprived primary neurons, and in activation of ribos omal S6 kinases. (C) 1998 Wiley-Liss, Inc.