Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage

Mikael J.L. Eliasson, Zhihong Huang, Robert J. Ferrante, Masao Sasamata, Mark E. Molliver, Solomon H. Snyder, Michael A. Moskowitz

Research output: Contribution to journalArticlepeer-review

320 Scopus citations


Nitric oxide (NO) is a new intercellular messenger that occurs naturally in the brain without causing overt toxicity. Yet, NO has been implicated as a mediator of cell death in cell death. One explanation is that ischemia causes overproduction of NO, allowing it to react with superoxide to form the potent oxidant peroxynitrite. To address this question, we used immunohistochemistry for citrulline, a marker for NO synthase activity, and 3-nitrotyrosine, a marker for peroxynitrite formation, in mice subjected to reversible middle cerebral artery occlusion. We show that ischemia triggers a marked augmentation in citrulline immunoreactivity but more so in the peri-infarct than the infarcted tissue. This increase is attributable to the activation of a large population (~80%) of the neuronal isoform of NO synthase (nNOS) that is catalytically inactive during basal conditions, indicating a tight regulation of physiological NO production in the brain. In contrast, 3- nitrotyrosine immunoreactivity is restricted to the infarcted tissue and is not present in the peri-infarct tissue. In nNOS(Δ/Δ) mice, known to be protected against ischemia, no 3-nitrotyrosine immunoreactivity is detected. Our findings provide a cellular localization for nNOS activation in association with ischemic stroke and establish that NO is not likely a direct neurotoxin, whereas its conversion to peroxynitrite is associated with cell death.

Original languageEnglish (US)
Pages (from-to)5910-5918
Number of pages9
JournalJournal of Neuroscience
Issue number14
StatePublished - Jul 15 1999


  • 3-nitrotyrosine
  • Citrulline
  • Ischemial
  • Nitric oxide
  • Nitric oxide synthase
  • Peroxynitrite

ASJC Scopus subject areas

  • General Neuroscience


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