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Pleiotropic effects of PI3K/Akt pathway in hippocampal neurons exposed to iron‐induced oxidative stress

PI3K/Akt pathway is a key component in synaptic plasticity and neuronal survival. The aim of this work was to investigate the participation of PI3K/Akt pathway and its outcome on different molecular targets such as GSK3β and FoxO transcription factors during mild oxidative stress triggered by iron overload. The exposure of mouse hippocampal neurons (HT22) to different concentrations of Fe2+ (25–200 μM) for 24 h led us to define a mild oxidative injury status (50 μM Fe2+) in which cell morphology showed typical changes of neuronal damage, with increased lipid peroxidation and cellular oxidant levels but no alterations of cellular viability. Under these experimental conditions, SOD1, SOD2 and Trx expression was diminished, catalase showed no changes, and HO1 was increased, with respect to the control. Simultaneously, both Akt and GSK3β phosphorylation was increased. Levels of phospho‐FoxO3a (inactive form) increased in the cytosolic fraction of cells treated with iron in a PI3K‐dependent manner. Moreover, PI3K and Akt translocated to the nucleus in response to oxidative stress. Iron‐overloaded cells harboring a contitutively active form of Akt showed decreased oxidants levels. Our results show that the activation of PI3K/Akt pathway during iron‐induced neurotoxicity regulates multiple targets such as GSK3β, FoxO transcriptional activity and the generation of reactive oxygen species.