Transient phosphatidylinositol 3-kinase inhibition protects immature primary cortical neurons from oxidative toxicity via suppression of extracellular signal-regulated kinase activation.
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.
Levinthal
David J
DJ
Center for Neuroscience and Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
DeFranco
Donald B
DB
D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020928:Mitogen-Activated Protein Kinases