Activation of Akt/FoxO and inactivation of MEK/ERK pathways contribute to induction of neuroprotection against transient global cerebral ischemia by delayed hypoxic postconditioning in adult rats

Abstract

Ischemic postconditioning, a series of mechanical interruptions of blood flow immediately after reperfusion, has been described in brain studies. However, hypoxic postconditioning (HPC) has never been reported in transient global cerebral ischemia (tGCI) adult rat model. The purpose of this study is to explore the effects of neuroprotection by delayed HPC against tGCI in adult rats and investigate underlying mechanisms involving the Akt/Forkhead transcription factor, class O (FoxO) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways. Postconditioning with 60-120 min hypoxia significantly reduced cell death in hippocampal CA1 subregion after 10 min of tGCI. Postconditioning was effective only when applied 1-2 days after tGCI. Nevertheless, the combination of hypoxic preconditioning and postconditioning provided no additive protection. Additionally, postconditioning increased phosphorylation of Akt and FoxOs after tGCI. Inhibiting phosphorylation of Akt and FoxOs with LY294002 suppressed the postconditioning-induced neuroprotection. In addition, postconditioning blocked the increase of MEK and ERK phosphorylation after tGCI. Inhibiting phosphorylation of MEK and ERK with U0126 attenuated neuronal damage after tGCI. These results suggest that delayed HPC exerts neuroprotection against tGCI-induced injury in adult rats. The activation of Akt/FoxO and inactivation of MEK/ERK pathways by postconditioning contributed to the induction of neuroprotection against tGCI.