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

Mirella Gonzalez-Zulueta, Alicia B. Feldman, Laura J. Klesse, Robert G. Kalb, James F. Dillman, Luis F. Parada, Ted M Dawson, Valina Dawson

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)436-441
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number1
DOIs
StatePublished - Jan 4 2000

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Proto-Oncogene Proteins p21(ras)
Ischemic Preconditioning
Nitric Oxide
Phosphotransferases
Oxygen
Glucose
Ischemia
Phosphatidylinositols
Pharmacology
Neurons
N-Methyl-D-Aspartate Receptors
Adenoviridae

ASJC Scopus subject areas

  • Genetics
  • General

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Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. / Gonzalez-Zulueta, Mirella; Feldman, Alicia B.; Klesse, Laura J.; Kalb, Robert G.; Dillman, James F.; Parada, Luis F.; Dawson, Ted M; Dawson, Valina.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 1, 04.01.2000, p. 436-441.

Research output: Contribution to journalArticle

Gonzalez-Zulueta, Mirella ; Feldman, Alicia B. ; Klesse, Laura J. ; Kalb, Robert G. ; Dillman, James F. ; Parada, Luis F. ; Dawson, Ted M ; Dawson, Valina. / Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 1. pp. 436-441.
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