Excitotoxicity is Required for Induction of Oxidative Stress and Apoptosis in Mouse Striatum by the Mitochondrial Toxin, 3-Nitropropionic Acid

Kim, Gyung Whan; Copin, Jean‐Christophe; Kawase, Makoto; Chen, Sylvia F.; Sato, Shuzo; Gobbel, Glenn T.; Chan, Pak H.

doi:10.1097/00004647-200001000-00016

Cited by 113 publications

(78 citation statements)

References 29 publications

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“…24,25 Recently, cellular O 2 ·Ϫ production using a HEt in situ detection method was reported in a variety of experimental models such as in vitro excitotoxin-treated cell culture, 10 in vivo permanent focal cerebral ischemia, 10,11 permanent cortical infarction, 26 transient global or focal ischemia, 7,27 or mitochondrial toxin injury. 28,29 There is evidence of HEt-specific oxidation by O 2 ·Ϫ , that HEt is oxidized to Et by O 2 ·Ϫ produced by activated leukocytes, 13 and that HEt is selectively oxidized to Et by O 2 ·Ϫ but not by other ROS in cultured hippocampal neurons. 14 Benov et al 30 suggest that HEt conversion to Et might be a useful tool for detecting O 2 ·Ϫ production, because HEt is rapidly oxidized to Et by O 2 ·Ϫ .…”

Section: Discussionmentioning

confidence: 99%

Manganese Superoxide Dismutase Deficiency Exacerbates Cerebral Infarction After Focal Cerebral Ischemia/Reperfusion in Mice

Kim

Kondo

Noshita

et al. 2002

Stroke

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227

136

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Background and Purpose-Superoxide anion radicals (O 2 ·Ϫ ) 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 ·Ϫ was developed to detect O 2 ·Ϫ production in a variety of experimental brain injury models. To clarify the role of O 2 ·Ϫ in the mechanism of ischemia/reperfusion, we investigated O 2 ·Ϫ 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 ·Ϫ production using specific HEt oxidation by O 2 ·Ϫ before and after ischemia/reperfusion. Furthermore, we compared O 2 ·Ϫ 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 ·Ϫ under physiological conditions. Cerebral ischemia/reperfusion produced O 2 ·Ϫ 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 ·Ϫ production and exacerbated cerebral infarction, worsening neurological deficits after ischemia/reperfusion. Conclusion-These results suggest that mitochondrial O 2 ·Ϫ 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.

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Section: Discussionmentioning

confidence: 99%

Manganese Superoxide Dismutase Deficiency Exacerbates Cerebral Infarction After Focal Cerebral Ischemia/Reperfusion in Mice

Kim

Kondo

Noshita

et al. 2002

Stroke

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227

136

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“…Interestingly, although tBHQ did not reduce damage to the striatal stroke core during transient MCAO, it significantly attenuated striatal neurodegeneration during 3-nitropropionic acid toxicity (Shih et al, 2005). Because 3-nitropropionic acid produces gradual and partial metabolic inhibition (Beal et al, 1993;Sato et al, 1997;Brouillet et al, 1998;Kim et al, 2000), it is in some ways similar to the salvageable cortical stroke penumbra.…”

Section: Nrf2 Dependency Of Tbhq-mediated Neuroprotectionmentioning

confidence: 99%

A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral IschemiaIn Vivo

Shih¹,

Li²,

Murphy³

2005

J. Neurosci.

390

289

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The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Previously, activation of this pleiotropic response was neuroprotective in cell culture models that simulate components of stroke damage. However, the role of Nrf2 in limiting stroke damage in vivo remained unclear. We report that Nrf2 activation protects the brain from cerebral ischemia in vivo. Acute (1-3 d) intracerebroventricular or intraperitoneal pretreatment with tert-butylhydroquinone (tBHQ), an Nrf2 activity inducer, reduced cortical damage and sensorimotor deficit at 24 h and even 1 month after ischemia-reperfusion in rats. Cortical glutathione levels robustly increased with tBHQ administration to rats and Nrf2-expressing mice, but not Nrf2 Ϫ/Ϫ mice. Basal and inducible activities of antioxidant/detoxification enzymes in Nrf2Ϫ/Ϫ mice were reduced when compared with Nrf2 ϩ/ϩ controls. Interestingly, larger infarcts were observed in Nrf2 Ϫ/Ϫ mice at 7 d after stroke, but not at 24 h, suggesting that Nrf2 may play a role in shaping the penumbra well after the onset of ischemia. Neuronal death caused by a "penumbral" model of stroke, using intracortical endothelin-1 microinjection, was attenuated by tBHQ administration to Nrf2 ϩ/ϩ , but not to Nrf2 Ϫ/Ϫ mice, confirming the Nrf2-specific action of tBHQ in vivo. We conclude that Nrf2 plays a role in modulating ischemic injury in vivo. Accordingly, Nrf2 activation by small molecule inducers may be a practical preventative treatment for stroke-prone patients.

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“…16 Detection of oxidized HEt is a useful tool to show ROS production because HEt is oxidized to ethidium mainly by the superoxide anion radical. 17,18 Two hundred microliters of HEt (stocked concentration, 100 mg/mL in dimethyl sulfoxide; diluted concentration, 1 mg/mL in PBS with sonication before use; Molecular Probes) was administrated intravenously 5 minutes before the induction of ischemia.…”

Section: Detection Of Oxidative Cellular Injury After Reperfusionmentioning

confidence: 99%

Early Decrease in DNA Repair Proteins, Ku70 and Ku86, and Subsequent DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice

Kim

Noshita

Sugawara

et al. 2001

Stroke

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Background and Purpose-Ku70 and Ku86, multifunctional DNA repair proteins, bind to broken DNA ends, including double-strand breaks, and trigger a DNA repair pathway. To investigate the involvement of these proteins in DNA fragmentation after ischemia/reperfusion, Ku protein expression was examined before and after transient focal cerebral ischemia (FCI) in mice. Methods-Adult male CD-1 mice were subjected to 60 minutes of FCI by intraluminal suture blockade of the middle cerebral artery. Ku protein expression was studied by immunohistochemistry and Western blot analysis. DNA fragmentation was evaluated by gel electrophoresis and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). The spatial relationship between Ku expression and DNA fragmentation was examined by double labeling with Ku and TUNEL after reperfusion. Results-Immunohistochemistry showed constitutive expression of Ku proteins in control brains. The number of Ku-expressing cells was decreased in the entire middle cerebral artery territory as early as 4 hours after reperfusion and remained reduced until 24 hours. Western blot analyses confirmed the significant reduction of these proteins (59.4% and 57.7% reduction in optical density at 4 hours of reperfusion from the normal level of Ku70 and Ku86 bands, respectively; PϽ0.001). DNA gel electrophoresis demonstrated DNA laddering 24 hours after reperfusion, but not at 4 hours. Double staining with Ku and TUNEL showed a concomitant loss of Ku immunoreactivity and TUNEL-positive staining. Conclusions-These results suggest that the early reduction of Ku proteins and the loss of defense against DNA damage may underlie the mechanism of DNA fragmentation after FCI.

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Excitotoxicity is Required for Induction of Oxidative Stress and Apoptosis in Mouse Striatum by the Mitochondrial Toxin, 3-Nitropropionic Acid

Cited by 113 publications

References 29 publications

Manganese Superoxide Dismutase Deficiency Exacerbates Cerebral Infarction After Focal Cerebral Ischemia/Reperfusion in Mice

Manganese Superoxide Dismutase Deficiency Exacerbates Cerebral Infarction After Focal Cerebral Ischemia/Reperfusion in Mice

A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral IschemiaIn Vivo

Early Decrease in DNA Repair Proteins, Ku70 and Ku86, and Subsequent DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice

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