Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: Activation of dual specificity phosphatase

Nobuya Okami, Purnima Narasimhan, Hideyuki Yoshioka, Hiroyuki Sakata, Gab Seok Kim, Joo Eun Jung, Carolina M. Maier, Pak H. Chan

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, prevents cell death after cerebral ischemia in animal models, but the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone protects neurons against ischemia. Mice treated with rosiglitazone were subjected to 60 minutes of focal ischemia followed by reperfusion. Rosiglitazone reduced infarct volume after ischemia and reperfusion. We show that this neuroprotective effect was reversed with a PPARγ antagonist. Western blot analysis showed a significant increase in expression of phosphorylated stress-activated protein kinases (c-Jun N-terminal kinase (JNK) and p38) in ischemic brain tissue. Rosiglitazone blocked this increase. Furthermore, we observed that rosiglitazone increased expression of the dual-specificity phosphatase 8 (DUSP8) protein and messenger RNA in ischemic brain tissue. Dual-specificity phosphatase 8 is a mitogen-activated protein kinase phosphatase that can dephosphorylate JNK and p38. Another key finding of the present study was that knockdown of DUSP8 in primary cultured cortical neurons that were subjected to oxygen-glucose deprivation diminished rosiglitazone's effect on downregulation of JNK phosphorylation. Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation.

Original languageEnglish
Pages (from-to)106-114
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number1
DOIs
Publication statusPublished - 2013 Jan

Keywords

  • c-Jun N-terminal kinase
  • cerebral ischemia
  • dual-specificity phosphatase 8
  • p38 mitogen-activated protein kinase
  • rosiglitazone

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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