Research for the mechanism of ischemic tolerance in neuronal cells

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To investigate the mechanism of ischemic tolerance, we first focused on the activity of Akt that was reported as a key enzyme of anti-apoptotic signaling. Sublethal ischemia gradually and persistently activated Akt in hippocampal CA1 region. Intra-cerebral ventricular infusion of wortmannin prior to preconditioning blocked both the increase in Akt activation and the neuroprotective action of preconditioning. Next we examined the activation of CREB that was one of the candidates for the target of Akt signaling. Phosphorylation and binding activity of CREB after sublethal ischemia was observed transiently. Inhibition of CREB-DNA binding by infusion of CRE-decoy into the cerebral ventricle resulted in failure of induction of ischemic tolerance. These results suggested that Akt signaling and CREB activation contributed to neuroprotective ischemic tolerance in CA1 pyramidal neurons. As these effects could not explain the entire mechanism of ischemic tolerance, we are going to keep on investigating other key molecules.