Decreased Akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus

Takayuki Kawano, Motohiro Morioka, Shigetoshi Yano, Jun ichiro Hamada, Yukitaka Ushio, Eishichi Miyamoto, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)


The authors recently reported that sodium orthovanadate rescues cells from delayed neuronal death in gerbil hippocampus after transient forebrain ischemia through phosphatidylinositol 3-kinase-protein kinase B (Akt) pathway (Kawano et al., 2001). In the current study, they demonstrated that the activation of FKHR, a Forkhead transcription factor and a substrate for Akt, preceded delayed neuronal death in CAI regions after transient forebrain ischemia. Adult Mongolian gerbils were subjected to 5-minute forebrain ischemia. Immunoblotting analysis with anti-phospho-FKHR antibody showed that phosphorylation of FKHR at serine-256 in the CAI region decreased immediately after and 0.5 and 1 hour after reperfusion. The dephosphorylation of FKHR was correlated with the decreased Akt activity. Intracerebroventricular injection of orthovanadate 30 minutes before ischemia inhibited dephosphorylation of FKHR after reperfusion, and blocked delayed neuronal death in the CAI region. Gel mobility shift analysis using nuclear extracts from the CAI region prepared immediately after reperfusion revealed increases in DNA binding activity for the FKHR-responsive element on the Fas ligand promoter. The orthovanadate injection administered before ischemia inhibited its binding activity. Two days after reperfusion, expression of Fas ligand increased in the CAI region and the orthovanadate injection inhibited this increased expression. These results suggest that the inactivation of Akt results in the activation of FKHR and, in turn, relates to the expression of Fas ligand in the CAI region after transient forebrain ischemia.

Original languageEnglish
Pages (from-to)926-934
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number8
Publication statusPublished - 2002
Externally publishedYes


  • Akt
  • Delayed neuronal death
  • FKHR
  • Forkhead transcription factors
  • Sodium orthovanadate
  • Transient forebrain ischemia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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