title: Nitric oxide-induced apoptosis in cultured rat astrocytes: protection by edaravone, a radical scavenger.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kitao
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Fujisaki
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takegawa
authors.forename: Ken
authors.initials: K
authors.lastname: Koda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077553:Edaravone; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D009599:Nitroprusside; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077553:Edaravone; D000983:Antipyrine