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The Journal of Neuroscience, July 15, 1999, 19(14):5910-5918
Neuronal Nitric Oxide Synthase Activation and Peroxynitrite
Formation in Ischemic Stroke Linked to Neural Damage
Mikael J. L.
Eliasson1, 2,
Zhihong
Huang4,
Robert J.
Ferrante5, 6,
Masao
Sasamata4,
Mark E.
Molliver2,
Solomon H.
Snyder1, 2, 3, and
Michael A.
Moskowitz4
Departments of 1 Pharmacology and Molecular Science,
2 Neuroscience, and 3 Psychiatry, Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205, 4 Stroke and Neurovascular Regulation Laboratory, Neurology
and Neurosurgery Services Massachusetts General Hospital, Charlestown,
Massachusetts 02129, 5 Departments of Neurology, Pathology,
and Psychiatry, Boston University School of Medicine, Boston,
Massachusetts 02118, and 6 Bedford Veterans Administration
Medical Center, GRECC Unit 182B, Bedford, Massachusetts 01730
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 / 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.
Key words:
citrulline; ischemial; peroxynitrite; 3-nitrotyrosine; nitric oxide; nitric oxide synthase; peroxynitrite
Copyright © 1999 Society for Neuroscience 0270-6474/99/19145910-09$05.00/0
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