p21ras Activation following hypoxia-ischemia in the newborn rat brain is dependent on nitric oxide synthase activity but p21ras does not contribute to neurologic injury

Mark S. Wainwright, Lisa A. Brennan, Maria L. Dizon, Stephen M. Black*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Hypoxia-ischemia (HI) in the perinatal period is associated with significant infant mortality and neurologic morbidity. Increase in the activity of nitric oxide synthase (NOS) and increased release of nitric oxide (NO) are cardinal events in the pathophysiology of stroke and perinatal asphyxia. Cell culture studies suggest that the GTP-binding protein p21ras (Ras) is activated by NO in an NMDA-receptor-dependent pathway. These findings imply that Ras may be activated in vivo by NO released in response to glutamate stimulation during HI. The contribution of downstream Ras activation to neurologic injury after perinatal HI is unknown. We used a postnatal day 7 rat model of perinatal hypoxia-ischemia to determine the response of Ras to HI, the role of NO in Ras activation and the effect of Ras inhibition on neurologic injury in vivo. Ras is activated in both hippocampus and cortex within 2 h after HI. This increase is prevented by treatment with the NOS inhibitor, aminoguanidine (AG) and by a farnesyl/protein transferase inhibitor, manumycin (MAN). Inhibition of NOS, but not Ras, significantly reduces neurologic injury after a 7-day recovery period. This data suggests that Ras is activated during the initiation of the cellular response to HI in both hippocampus and cortex and that this activation is NO-dependent. Ras does not, however, contribute to the pathophysiologic NO-dependent mechanisms of neurologic injury in this model.

Original languageEnglish (US)
Pages (from-to)79-85
Number of pages7
JournalDevelopmental Brain Research
Volume146
Issue number1-2
DOIs
StatePublished - Dec 19 2003

Keywords

  • Brain
  • Hypoxia-ischemia
  • Neonate
  • Nitric oxide synthase
  • Ras

ASJC Scopus subject areas

  • Developmental Neuroscience
  • Developmental Biology

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