TY - JOUR
T1 - Decreased Akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus
AU - Kawano, Takayuki
AU - Morioka, Motohiro
AU - Yano, Shigetoshi
AU - Hamada, Jun ichiro
AU - Ushio, Yukitaka
AU - Miyamoto, Eishichi
AU - Fukunaga, Kohji
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Akt
KW - Delayed neuronal death
KW - FKHR
KW - Forkhead transcription factors
KW - Sodium orthovanadate
KW - Transient forebrain ischemia
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U2 - 10.1097/00004647-200208000-00004
DO - 10.1097/00004647-200208000-00004
M3 - Article
C2 - 12172378
AN - SCOPUS:0036325163
VL - 22
SP - 926
EP - 934
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 8
ER -