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.
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.
Sarker
Krishna P
KP
Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, Kagoshima-890, Japan. kpsarker@ucalgary.ca
Biswas
Kamal K
KK
Rosales
Jesusa L
JL
Yamaji
Kazuyo
K
Hashiguchi
Teruto
T
Lee
Ki-Young
KY
Maruyama
Ikuro
I
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D001393:Azoles / Q000494:pharmacology*; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018834:Chaperonin 60 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D054833:Isoindoles; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D016716:PC12 Cells; D011419:Propidium / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000378:metabolism; D018038:Sodium Selenite / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014810:Vitamin E / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D017304:Annexin A5; D001393:Azoles; D002070:Butadienes; D018834:Chaperonin 60; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D054833:Isoindoles; D020030:Nitric Oxide Donors; D009570:Nitriles; D016566:Organoselenium Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C113580:U 0126; D014810:Vitamin E; D009599:Nitroprusside; D009569:Nitric Oxide; D011419:Propidium; C042986:ebselen; D012694:Serine; D045304:Cytochromes c; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D018038:Sodium Selenite; D004229:Dithiothreitol