Pathophysiological relevance of forkhead transcription factors in brain ischemia

Forkhead box transcription factor, class 0 (FOXO) is a mammalian homologue of DAF-16, which is known to regulate the lifespan of Caenorhabditis elegans and includes subfamiies of forkhead transcription factors such as FOXO1 (FKHR). FOXO3 (FKHRL1), FOXO4 (AFX) and FOXO6. All these FOXO members are expressed in the brain with different spatial patterns. FOXO1 is phosphorylated on three sites (Thr-24, Ser-256 and Ser-319) in phosphatidylinositol 3-kinase (PI3-K)/Akt-dependenr manner, thereby inhibiting apoptosis signals. We here documented dephosphorylation of FOXO1, FOXO3 and FOXO4 following transient forebrain ischemia with its concomitant translocation into the nucleus in neurons in the gerbil and mouse brains. The dephosphorylarion of FOXO1 following brain ischemia is in part mediated by constirutively active calcineurin in the mouse hippocampus. The activation of FOXOs preceded delayed neuronal death in the vulnerable hippocampal regions following ischemic brain injury. The FOXOl activation is accompanied by an increase in DNA binding activity for FOXO1-responsive element on the Fas ligand promoter. Thus, downstream targets induced by FOXOl include Fas ligand and Bcl-2-interacting mediator of cell death (Bim) in the brain ischemia. Accumulating evidence documented how FOXO activation is involved in the mechanisms of ischemic cell death. In this chapter, we document the activation mechanism of FOXO factors following brain ischemia and deline their downstream targets underlying neuronal death. The pathophysiological relevance of crosstalk between FOXOs and calcineurmn pathways is also discussed. Finally, we propose therapeutic perspectives to rescue neurons from delayed neuronal death by promoting the Akt signaling. Vanadium compounds, protein tyrosine phosphatase inhibitor, up-regulates Akt activity in the brain and thereby rescues neurons from delayed neuronal death by inhibiting FOXO-dependent and -independent death signals in neurons.