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J. Biol. Chem., Vol. 279, Issue 12, 11206-11213, March 19, 2004

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Transient Phosphatidylinositol 3-Kinase Inhibition Protects Immature Primary Cortical Neurons from Oxidative Toxicity via Suppression of Extracellular Signal-regulated Kinase Activation^*

David J. Levinthal and Donald B. DeFranco¶

From the Center for Neuroscience and Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Oxidative stress has been shown to underlie a diverse range of neuropathological conditions. Glutamate-induced oxidative toxicity is a well described model of oxidative stress-induced neurodegeneration that relies upon the ability of extracellular glutamate to inhibit a glutamate/cystine antiporter, which results in a depletion of intracellular cysteine and the blockade of continued glutathione synthesis. Glutathione depletion leads to a gradual toxic accumulation of reactive oxygen species. We have previously determined that glutamate-induced oxidative toxicity is accompanied by a robust increase in activation of the mitogen-activated protein kinase (MAPK) member extracellular-signal regulated kinase (ERK) and that this activation is essential for neuronal cell death. This study demonstrates that delayed ERK activation is dependent upon the activity of phosphoinositol-3 kinase (PI3K) and that transient but not sustained PI3K inhibition leads to significant protection of neurons from oxidative stress-induced neurodegeneration. Furthermore, we show that transient PI3K inhibition prevents the delayed activation of MEK-1, a direct activator of ERK, during oxidative stress. Thus, this study is the first to demonstrate a novel level of cross-talk between the PI3K and ERK pathways in cultured immature cortical neuronal cultures that contributes to the unfolding of a cell death program. The PI3K pathway, therefore, may serve opposing roles during the progression of oxidative stress in neurons, acting at distinct kinetic phases to either promote or limit a slowly developing program of cell death.

Received for publication, December 29, 2003

^* This work was supported by National Institutes of Health Grant R01 NS38319 (to D. B. D.), National Institute of Health Predoctoral Institutional NRSA Grant T32 NS07433 (to D. J. L.), and National Institutes of Health Predoctoral Individual NRSA Grant F30 NS43824 (to D. J. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology, University of Pittsburgh School of Medicine, E1352 BST, Pittsburgh, PA 15261. Tel.: 412-624-4259; Fax: 412-648-1945; E-mail: dod1{at}pitt.edu.

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