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What Is the Role of Nitric Oxide in Ischemic Stroke?

The multifunctional molecule nitric oxide (NO) is an inorganic gas produced in neurons, glia, endothelial cells, and macrophages. Its production is mediated by one of the isoforms of the enzyme nitric oxide synthetase (NOS), which converts L-arginine and oxygen to NO and citrulline. Whether NO functions as either a neuroprotectant or neurotoxin is determined by the NOS isoform. The main effects of NO in ischemic stroke remain controversial, because opposite effects have been demonstrated in experimental models. Because the extremely short half-life of NO makes detection in the brain difficult, these authors sought to determine the predominant role of NO in acute ischemic stroke by studying stable NO metabolites (NO-m) in the cerebrospinal fluid (CSF).

Subjects were 102 persons with acute stroke and 24 controls. The strokes were of various etiologies and sizes. NO generation was calculated by measuring NO-m in the CSF by colorimetric assay. In the stroke patients, CSF samples were obtained within 24 hours of symptom onset. Each stroke patient also underwent serial clinical examinations and CT measurements of infarct volume. Glutamate, an excitatory amino acid implicated as cytotoxic in cerebral ischemia, was also measured in the CSF.

CSF NO-m concentrations were significantly higher in stroke patients than in controls. Although NO-m concentrations did not differ by stroke subtype, the NO-m concentration did correlate somewhat with infarct volume. CSF NO-m concentrations were significantly higher in stroke patients who subsequently suffered early neurologic worsening than in those with a stable course. The effect of NO was independent of other important predictors of progressing stroke, such as hyperthermia, high serum glucose, early infarct signs on CT, and infections within the first week of hospitalization. The effect of NO was also independent of glutamate concentration.

Comment: This well-designed clinical study is important for several reasons: It underscores the important role of NO in stroke, as it suggests that NO in this setting has predominantly cytotoxic effects. Furthermore, the cytotoxic effects may not be mediated by glutamate mechanisms. The authors hypothesize that NO, generated by inducible NOS in the core of an infarct, diffuses outward to directly exert neurotoxic effects on the vulnerable neighboring neurons in the penumbra, thus accounting for the fact that neurologic worsening may occur in the absence of relevant changes in cerebral blood flow. The establishment of CSF markers for NOS isoforms will allow this provocative hypothesis to be tested.

— GE Tietjen

Gretchen E. Tietjen, MD, is Associate Professor and Chair, Department of Neurology, Medical College of Ohio, Toledo, OH.

Published in Journal Watch Neurology July 1, 2000

Citation(s):

Castillo J et al. Nitric oxide-related brain damage in acute ischemic stroke. Stroke 2000 Apr 31 852 -857.

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