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

Krishna P. Sarker, Kamal K. Biswas, Jesusa L. Rosales, Kazuyo Kegan, Teruto Hashiguchi, Ki Young Lee, Ikuro Maruyama

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1345-1353
Number of pages9
JournalJournal of Neurochemistry
Volume87
Issue number6
StatePublished - Dec 2003
Externally publishedYes

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Mitogen-Activated Protein Kinase 1
PC12 Cells
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Nitric Oxide
Phosphotransferases
Chemical activation
Apoptosis
Phosphorylation
Nitroprusside
Heterocyclic Compounds
ebselen
Nitric Oxide Donors
JNK Mitogen-Activated Protein Kinases
Phosphatidylserines
Cell death
Cytotoxicity
Selenium
Cytochromes c
Sulfhydryl Compounds

Keywords

  • Apoptosis
  • Ebselen
  • MAP kinases
  • Nitric oxide
  • PC12 cells

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Sarker, K. P., Biswas, K. K., Rosales, J. L., Kegan, K., Hashiguchi, T., Lee, K. Y., & Maruyama, I. (2003). 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. Journal of Neurochemistry, 87(6), 1345-1353.

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. / Sarker, Krishna P.; Biswas, Kamal K.; Rosales, Jesusa L.; Kegan, Kazuyo; Hashiguchi, Teruto; Lee, Ki Young; Maruyama, Ikuro.

In: Journal of Neurochemistry, Vol. 87, No. 6, 12.2003, p. 1345-1353.

Research output: Contribution to journalArticle

Sarker, KP, Biswas, KK, Rosales, JL, Kegan, K, Hashiguchi, T, Lee, KY & Maruyama, I 2003, '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', Journal of Neurochemistry, vol. 87, no. 6, pp. 1345-1353.
Sarker, Krishna P. ; Biswas, Kamal K. ; Rosales, Jesusa L. ; Kegan, Kazuyo ; Hashiguchi, Teruto ; Lee, Ki Young ; Maruyama, Ikuro. / 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. In: Journal of Neurochemistry. 2003 ; Vol. 87, No. 6. pp. 1345-1353.
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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.",
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AU - Sarker, Krishna P.

AU - Biswas, Kamal K.

AU - Rosales, Jesusa L.

AU - Kegan, Kazuyo

AU - Hashiguchi, Teruto

AU - Lee, Ki Young

AU - Maruyama, Ikuro

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