Journal Article

Iron-Induced Oxidative Injury Differentially Regulates PI3K/Akt/GSK3β Pathway in Synaptic Endings from Adult and Aged Rats

Romina María Uranga, Norma María Giusto and Gabriela Alejandra Salvador

in Toxicological Sciences

Volume 111, issue 2, pages 331-344
Published in print October 2009 | ISSN: 1096-6080
Published online July 2009 | e-ISSN: 1096-0929 | DOI:
Iron-Induced Oxidative Injury Differentially Regulates PI3K/Akt/GSK3β Pathway in Synaptic Endings from Adult and Aged Rats

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In this work we study the state of phosphoinositide-3-kinase/Akt/glycogen synthase kinase 3 beta (PI3K/Akt/GSK3β) signaling during oxidative injury triggered by free iron using cerebral cortex synaptic endings isolated from adult (4-month-old) and aged (28-month-old) rats. Synaptosomes were exposed to FeSO4 (50μM) for different periods of time and synaptosomal viability and the state of the PI3K/Akt/GSK3β pathway were evaluated in adult and aged animals. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction and lactate dehydrogenase leakage were significantly affected in both age groups. However, aged animals showed a greater susceptibility to oxidative stress. In adults, Akt was activated after a brief exposure time (5 min), whereas in aged animals activation occurred after 5 and 30 min of incubation with the metal ion. GSK3β phosphorylation showed the same activation pattern as that observed for Akt. Both Akt and GSK3β phosphorylation were dependent on PI3K activation. Extracellular signal–regulated kinases 1 and 2 (ERK1/2) activation was temporally coincident with Akt activation and was PI3K dependent in adults, whereas ERK1/2 activation in aged rats was higher than that observed in adults and showed no dependence on PI3K activity. We demonstrate here that synaptic endings from adult and aged animals subjected to iron-induced neurotoxicity show a differential profile in the activation of PI3K/Akt/GSK3β. Our results strongly suggest that the increased susceptibility of aged animals to oxidative injury provokes a differential modulation of key signaling pathways involved in synaptic plasticity and neuronal survival.

Keywords: synaptic endings; PI3K; Akt; oxidative stress; iron; neurotoxicity

Journal Article.  7085 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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