Requirement for nitric oxide activation of p21ras/extracellular regulated kinase in neuronal ischemic preconditioning

被引:262
作者
Gonzalez-Zulueta, M
Feldman, AB
Klesse, LJ
Kalb, RG
Dillman, JF
Parada, LF
Dawson, TM
Dawson, VL
机构
[1] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21287 USA
[2] Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21287 USA
[3] Johns Hopkins Univ, Dept Physiol, Sch Med, Baltimore, MD 21287 USA
[4] Univ Texas, Ctr Dev Biol, Dallas, TX 75235 USA
[5] Yale Univ, Dept Neurol, New Haven, CT 06520 USA
关键词
D O I
10.1073/pnas.97.1.436
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 Pas activity is necessary and sufficient far OGD tolerance in neurons, Pharmacological inhibition of Pas, as well as a dominant negative mutant Pas, block OGD preconditioning whereas a constitutively active form of Pas 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 Pas 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.
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页码:436 / 441
页数:6
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