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 been shown to precede apoptosis of PC12 pheochromocytoma cells induced by withdrawal of trophic factors. To investigate the possible role of p38 in neuronal apoptosis, we tested the effect of two selective p38 inhibitors, the pyridinyl imidazole compounds SB203580 and SB202190, on different populations of chick embryonic neurons in vitro. Both substances promoted the in vitro survival of sensory, sympathetic, ciliary and motor neurons in a dose-dependent fashion. When assayed in nerve growth factor-stimulated PC12 cells, SB203580 pretreatment inhibited the activation of both ribosomal S6 kinases-1 and -2 with the same IC50 (approximately 30 microM) that inhibited apoptosis in primary neurons. Thus, p38 inhibitor-sensitive pathways may be involved in apoptosis of neurotrophic factor-deprived primary neurons, and in activation of ribosomal S6 kinases.
Horstmann
S
S
Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Munich, Germany.
Kahle
P J
PJ
Borasio
G D
GD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D013233:Stellate Ganglion / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D009414:Nerve Growth Factors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512963:Rps6ka1 protein, rat; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole