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Ebselen inhibits NO‐induced apoptosis of differentiated PC12 cells via inhibition of ASK1‐p38 MAPK‐p53 and JNK signaling and activation of p44/42 MAPK and Bcl‐2
Author(s) -
Sarker Krishna P.,
Biswas Kamal K.,
Rosales Jesusa L.,
Yamaji Kazuyo,
Hashiguchi Teruto,
Lee KiYoung,
Maruyama Ikuro
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02096.x
Subject(s) - ebselen , p38 mitogen activated protein kinases , microbiology and biotechnology , phosphorylation , protein kinase a , mapk/erk pathway , kinase , chemistry , apoptosis , ask1 , mitogen activated protein kinase , signal transduction , sh sy5y , biology , biochemistry , oxidative stress , mitogen activated protein kinase kinase , cell culture , superoxide dismutase , glutathione peroxidase , genetics , neuroblastoma
Ebselen, a selenium‐containing heterocyclic compound, prevents ischemia‐induced cell death. However, the molecular mechanism through which ebselen exerts its cytoprotective effect remains to be elucidated. Using sodium nitroprusside (SNP) as a nitric oxide (NO) donor, we show here that ebselen potently inhibits NO‐induced apoptosis of differentiated PC12 cells. This was associated with inhibition of NO‐induced phosphatidyl Serine exposure, cytochrome c release, and caspase‐3 activation by ebselen. Analysis of key apoptotic regulators during NO‐induced apoptosis of differentiated PC12 cells showed that ebselen blocks the activation of the apoptosis signaling‐regulating kinase 1 (ASK1), and inhibits phosphorylation of p38 mitogen‐activated protein kinase (MAPK) and c‐jun N‐terminal protein kinase (JNK). Moreover, ebselen inhibits NO‐induced p53 phosphorylation at Ser15 and c‐Jun phosphorylation at Ser63 and Ser73. It appears that inhibition of p38 MAPK and p53 phosphorylation by ebselen occurs via a thiol‐redox‐dependent mechanism. Interestingly, ebselen also activates p44/42 MAPK, and inhibits the downregulation of the antiapoptotic protein Bcl‐2 in SNP‐treated PC12 cells. Together, these findings suggest that ebselen protects neuronal cells from NO cytotoxicity by reciprocally regulating the apoptotic and antiapoptotic signaling cascades.