title: Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress.
abstract: The PI3K/Akt pathway is a key component in synaptic plasticity and neuronal survival. The aim of this work was to investigate the participation of the PI3K/Akt pathway and its outcome on different molecular targets such as glycogen synthase kinase 3β (GSK3β) and Forkhead box-O (FoxO) transcription factors during mild oxidative stress triggered by iron overload. The exposure of mouse hippocampal neurons (HT22) to different concentrations of Fe(2+) (25-200 μm) for 24 h led us to define a mild oxidative injury status (50 μm Fe(2+)) in which cell morphology showed changes typical of neuronal damage with increased lipid peroxidation and cellular oxidant levels but no alteration of cellular viability. There was a simultaneous increase in both Akt and GSK3β phosphorylation. 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 constitutively active form of Akt showed decreased oxidants levels. Indeed, GSH synthesis under oxidative stress conditions was regulated by activated Akt. Our results show that activation of the PI3K/Akt pathway during iron-induced neurotoxicity regulates multiple targets such as GSK3β, FoxO transcriptional activity, and glutathione metabolism, thus modulating the neuronal response to oxidative stress.
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur, 8000 Bahía Blanca, Argentina.
authors.forename: Romina María
authors.initials: RM
authors.lastname: Uranga
authors.forename: Sebastián
authors.initials: S
authors.lastname: Katz
authors.forename: Gabriela Alejandra
authors.initials: GA
authors.lastname: Salvador
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007501:Iron; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Akt; FoxO; Iron; Neurodegeneration; Oxidative stress