Nitric oxide induces apoptosis-like cell death in cultured astrocytes, but the exact mechanism is not known. This study further characterized the mechanism of nitric oxide-induced cytotoxicity, and examined the effect of edaravone, a radical scavenger, on cytotoxicity. Treatment of cultured rat astrocytes with sodium nitroprusside (SNP), a nitric oxide donor, for 72 h, decreased cell viability by causing apoptosis-like cell death. The injury was accompanied by increases in the production of reactive oxygen species and in the level of nuclear apoptosis-inducing factor, but not in caspase activity. SNP-induced cytotoxicity was blocked by the c-jun N-terminal protein kinase (JNK) inhibitor SP600125 (20 microM), the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 (20 microM), and the extracellular signal-regulating kinase (ERK) inhibitor U0126 (10 microM), and the nitric oxide donor stimulated the phosphorylation of p38 MAP kinase, JNK, and ERK. Edaravone (10 microM) protected astrocytes against SNP-induced cell injury and it inhibited SNP-induced phosphorylation of p38 MAP kinase, JNK, and ERK, and the production of reactive oxygen species. Edaravone also attenuated SNP-induced increase in nuclear apoptosis-inducing factor levels. These results suggest that MAP kinase pathways play a key role in nitric oxide-induced apoptosis and that edaravone protects against nitric oxide-induced cytotoxicity by inhibiting nitric oxide-induced MAP kinase activation in astrocytes.
Copyright (c) 2007 Wiley-Liss, Inc.