Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice: Implications for the production and role of superoxide radicals

Gyung W. Kim, Takeo Kondo, Nobuo Noshita, Pak H. Chan

Research output: Contribution to journalArticlepeer-review

209 Citations (Scopus)

Abstract

Background and Purpose - Superoxide anion radicals (O2-) are implicated in ischemia/reperfusion injury, although a direct relationship has not been elucidated. Recently, a specific method of hydroethidine (HEt) oxidation by O2- was developed to detect O2- production in a variety of experimental brain injury models. To clarify the role of O2- in the mechanism of ischemia/reperfusion, we investigated O2- 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 O2- production using specific HEt oxidation by O2- before and after ischemia/reperfusion. Furthermore, we compared O2- 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 O2- under physiological conditions. Cerebral ischemia/reperfusion produced O2- prominently in neurons shortly after reperfusion, followed by a delayed increase in endothelial cells. A deficiency in MnSOD in mutant mice increased mitochondrial O2- production and exacerbated cerebral infarction, worsening neurological deficits after ischemia/reperfusion. Conclusion - These results suggest that mitochondrial O2- 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.

Original languageEnglish
Pages (from-to)809-815
Number of pages7
JournalStroke
Volume33
Issue number3
DOIs
Publication statusPublished - 2002

Keywords

  • Cerebral ischemia, transient
  • Mice, transgenic
  • Oxidative stress
  • Superoxide dismutase

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialised Nursing

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