[Signal transduction and development of drug for brain ischemic insult].
The author reported that sodium orthovanadate rescues cells from delayed neuronal death in gerbil hippocampus after transient forebrain ischemia though phosphatidylinositol 3 kinase/Akt pathway. We here demonstrated that the activation of FKHR, a Forkhead transcription factor and a substrate for Akt, precedes the delayed neuronal death in CA1 regions after transient forebrain ischemia. The phosphorylation of FKHR at serine-256 in the CA1 region decreased immediately after reperfusion. The dephosphorylation of FKHR was correlated with the decreased Akt activity. Intracerebroventricular injection of orthovanadate 30 min before ischemia inhibited dephosphorylation of FKHR after reperfusion, and block delayed neuronal death in the CA1 regions. Two days after reperfusion, expression of Fas ligand increased in the CA1 region and the orthovanadate injection inhibited this increased expression. Furthermore, sublethal ischemia gradually and persistently stimulated the phosphorylation of Akt-Ser-473 in the CA1 region after reperfusion. The preceded sublethal ischemia prevented the delayed neuronal death induced by the lethal ischemic conditions. Intracerebroventricular injection of wortmannin before preconditioning blocked both the increased in Akt-Ser-473 phosphorylation and the neuroprotective action of preconditioning. These results suggested that the inactivation of Akt results in the activation of FKHR and, in turn, relates to the expression of Fas ligand in the hippocampal CA1 region after transient forebrain ischemia. The prevention of Akt inactivation by treatment with orthovanadate is a potential therapeutic strategy for neuroprotection in brain ischemic insult. Thus PI3-kinase/Akt pathway and its downstream molecules are potential targets for drug development in the brain ischemic insult.
Fukunaga
Kohji
K
Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan.
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D005849:Gerbillinae; D018696:Neuroprotective Agents / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014638:Vanadates / Q000627:therapeutic use
D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D014638:Vanadates; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt