TY - JOUR
T1 - Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice
T2 - Implications for the production and role of superoxide radicals
AU - Kim, Gyung W.
AU - Kondo, Takeo
AU - Noshita, Nobuo
AU - Chan, Pak H.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Cerebral ischemia, transient
KW - Mice, transgenic
KW - Oxidative stress
KW - Superoxide dismutase
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U2 - 10.1161/hs0302.103745
DO - 10.1161/hs0302.103745
M3 - Article
C2 - 11872908
AN - SCOPUS:0036192957
VL - 33
SP - 809
EP - 815
JO - Stroke
JF - Stroke
SN - 0039-2499
IS - 3
ER -