CPI-1189 inhibits interleukin 1 beta-induced p38-mitogen-activated proteinkinase phosphorylation: an explanation for its neuroprotective properties?

The p38 mitogen-activated protein kinase (p38-MAPK) is a central enzyme in one of the major protein kinase cascades that regulate proapoptotic and pro inflammatory signal transduction. p38-MAPK is activated by receptor/ligand recognition events or by exposure to extracellular stressors, including oxi dative stress. Activation of p38-MAPK is affected by dual phosphorylation o n a specific inhibitory domain. Dual phosphorylation causes a structural ch ange in the p38-MAPK enzyme which allows binding of ATP and target substrat e. Agents which block ATP docking to phosphoactivated p38-MAPK are being in vestigated for treatment of inflammatory diseases and neurodegenerative pat hologies. An alternative strategy for p38-MAPK antagonism would be the inhi bition of p38-MAPK phosphoactivation. We now report potent inhibition of p3 8-MAPK phosphorylation by a synthetic benzamide (CPI-1189) which displays p rotective action against tumor necrosis factor-alpha (TNF alpha)-induced ne urodegeneration. In primary astrocytes treated with interleukin 1 beta (IL1 beta), CPI-1189 inhibits p38-MAPK phosphorylation at concentrations of 10 nM or less. While the precise molecular target of CPI-1189 remains unknown, these findings suggest a novel mechanism for the neuroprotective propertie s of the compound. These findings also indicate that antagonism of the p38- MAPK may be achieved through pharmacological inhibition of p38-MAPK phospho rylation, a strategy that is conceptually distinct from direct inhibition o f ATP binding to the active enzyme. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.