Affiliation:
1. From the Department of Neurosurgery, Department of Neurology & Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, Calif.
Abstract
Background and Purpose
—
Superoxide anion radicals (O
2
·−
) are implicated in ischemia/reperfusion injury, although a direct relationship has not been elucidated. Recently, a specific method of hydroethidine (HEt) oxidation by O
2
·−
was developed to detect O
2
·−
production in a variety of experimental brain injury models. To clarify the role of O
2
·−
in the mechanism of ischemia/reperfusion, we investigated O
2
·−
production after ischemia/reperfusion and ischemia/reperfusion injury in mutant mice deficient in mitochondrial manganese superoxide dismutase (MnSOD) and in wild-type littermates.
Methods
—
Ischemia/reperfusion was performed for 60 minutes using intraluminal suture blockade of the middle cerebral artery in the mutant or wild-type mice. We evaluated fluorescent kinetics of HEt or ethidium, the oxidized form of HEt, in brains after an intravenous injection of HEt, followed by measurement of cellular O
2
·−
production using specific HEt oxidation by O
2
·−
before and after ischemia/reperfusion. Furthermore, we compared O
2
·−
production and subsequent infarct volume in the mice using triphenyltetrazolium chloride after ischemia/reperfusion.
Results
—
HEt oxidation to ethidium is primarily a result of mitochondrially produced O
2
·−
under physiological conditions. Cerebral ischemia/reperfusion produced O
2
·−
prominently in neurons shortly after reperfusion, followed by a delayed increase in endothelial cells. A deficiency in MnSOD in mutant mice increased mitochondrial O
2
·−
production and exacerbated cerebral infarction, worsening neurological deficits after ischemia/reperfusion.
Conclusion
—
These results suggest that mitochondrial O
2
·−
production may be a critical step underlying the mechanism of ischemia/reperfusion injury and that MnSOD may protect against ongoing oxidative cell death after ischemia/reperfusion.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Advanced and Specialized Nursing,Cardiology and Cardiovascular Medicine,Neurology (clinical)
Cited by
221 articles.
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