NDLI: Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning.

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Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning.

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Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Feldman, A. B. Dawson, T. M. Dillman, J. F. Kalb, R. G. Dawson, V. L. Parada, L. F. Gonzalez-zulueta, M. Klesse, L. J.
Description	Author Affiliation: Gonzalez-Zulueta M ( Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.);
Abstract	The mechanisms underlying neuronal ischemic preconditioning, a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia, are poorly understood. Ischemia can be modeled in vitro by oxygen-glucose deprivation (OGD). We report here that OGD preconditioning induces p21(ras) (Ras) activation in an N-methyl-D-aspartate receptor- and NO-dependent, but cGMP-independent, manner. We demonstrate that Ras activity is necessary and sufficient for OGD tolerance in neurons. Pharmacological inhibition of Ras, as well as a dominant negative mutant Ras, block OGD preconditioning whereas a constitutively active form of Ras promotes neuroprotection against lethal OGD insults. In contrast, the activity of phosphatidyl inositol 3-kinase is not required for OGD preconditioning because inhibition of phosphatidyl inositol 3-kinase with a chemical inhibitor or with a dominant negative mutant does not have any effect on the development of OGD tolerance. Furthermore, using recombinant adenoviruses and pharmacological inhibitors, we show that downstream of Ras the extracellular regulated kinase cascade is required for OGD preconditioning. Our observations indicate that activation of the Ras/extracellular regulated kinase cascade by NO is a critical mechanism for the development of OGD tolerance in cortical neurons, which may also play an important role in ischemic preconditioning in vivo.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	1
Volume Number	97
Language	English
Publisher	National Academy of Sciences
Publisher Date	2000-02-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Ischemic Preconditioning Mitogen-Activated Protein Kinases Metabolism Nitric Oxide Pharmacology Proto-Oncogene Proteins P21(ras) Adenoviridae Anaerobiosis Animals Brain Calcium Cells, Cultured Chromones Glucose Deficiency Morpholines Oxygen Phosphatidylinositol 3-Kinases Phosphorylation Receptors, N-Methyl-D-Aspartate Signal Transduction Simplexvirus Genetics Transfection Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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