Preconditioning prevents ischemia-induced neuronal death through persistent Akt activation in the penumbra region of the rat brain

A brief period of ischemia, i.e. preconditioning of the middle cerebral artery territory, induces ischemic tolerance reducing the cerebral infarction volume caused by subsequent lethal ischemia. Nevertheless, little is known about the molecular mechanisms underlying this phenomenon. In the present study, we examined the involvement of the activation of Akt, a serine/threonine kinase, in the cerebral ischemic tolerance. Western blot analysis showed that Akt was activated in both non-preconditioned and preconditioned groups after ischemia for 1 hr, but the activation was long-lasting in the preconditioned rats. Immunohistochemical analysis demonstrated that the preconditioning-induced preventive effect on a rapid decrease in the activation level of Akt was due to the persistent activation of Akt in the penumbra region. In addition, TUNEL staining demonstrated that the preconditioning treatment inhibited the augmentation of neuronal death probably through apoptosis in the penumbra region to prevent the spread of infarction. Since the activation of Akt has been reported to protect cells from stress, the present results suggest that the preconditioning-induced persistent activation of Akt in the penumbra region plays an important role in ischemic tolerance of the brain.