We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
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.
- Authors
Sarker, Krishna P.; Biswas, Kamal K.; Rosales, Jesusa L.; Yamaji, Kazuyo; Hashiguchi, Teruto; Leet, Ki-young; Maruyama, Ikuro
- Abstract
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.
- Subjects
HETEROCYCLIC compounds; SELENIUM; APOPTOSIS; NITRIC oxide; CELL death; NEUROCHEMISTRY; NEUROBIOLOGY
- Publication
Journal of Neurochemistry, 2003, Vol 87, Issue 6, p1345
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1046/j.1471-4159.2003.02096.x