Mitogen-activated protein kinase pathway mediates peroxynitrite-induced apoptosis in human dopaminergic neuroblastoma SH-SY5Y cells

Peroxynitrite, a product of nitric oxide and super-oxide, is one of the most potent oxidants and it has been suggested to be involved in many neurodegenerative disorders. The mechanism of the cytotoxicity by peroxynitrite was examined using 3-morpholino-sydonimine (SIN-1) as a peroxynitrite donor and SH-SY5Y cells as a model of dopamine neurons. SIN-1 was found to induce apoptotic cell death with typical nucleosomal DNA fragmentation with activation of caspase 3-like proteases. The signal transduction of apoptosis was studied in concern to mitogen-activated protein kinases (MAPKs). After SIN-1 treatment, phosphorylation of p38 was detected, followed by that of Erk, SB202190, an inhibitor of p38, suppressed Erk phosphorylation to the basal level and partially reduced the activation of caspase 3-like proteases and also the cell death. These results suggest that peroxynitrite may activate p38 MAPK pathway to induce apoptosis in dopamine cells via activation of caspase 3-like proteases. (C) 1999 Academic Press.