Nitric oxide-induced apoptosis in cultured rat astrocytes: Protection by edaravone, a radical scavenger

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 mu M), the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 (20 mu M), and the extracellular signal-regulating kinase (ERK) inhibitor U0126 (10 mu M), and the nitric oxide donor stimulated the phosphorylation of p38 MAP kinase, JNK, and ERK. Edaravone (10 mu M) 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. (c) 2007 Wiley-Liss, Inc.