Oxidants, antioxidants and the ischemic brain

Warner, David S.; Sheng, Huaxin; Batinić‐Haberle, Ines

doi:10.1242/jeb.01022

Cited by 539 publications

(383 citation statements)

References 156 publications

(137 reference statements)

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“…60 -64 Such injury is mediated by reactive oxygen and nitrogen species, including the superoxide ion, hydrogen peroxide, hydroxyl radical, nitric oxide, and peroxynitrite, 61,63,65 Glutamate-mediated excitotoxicity, which leads to an increase in intracellular calcium, induces several endogenous enzymes that produce free radicals, including nitric oxide synthase, xanthine oxidase, and the phospholipase A 2 -cyclooxygenase pathway. 63 Such changes in intracellular calcium also perturb mitochondrial function, leading to leakage of superoxide.…”

Section: Oxidative Damagementioning

confidence: 99%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

143

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Summary: Traumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBIinflammation, oxidative injury, and iron-induced damage -and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.

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Section: Oxidative Damagementioning

confidence: 99%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

143

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“…Peroxynitrite (ONOO − ) is a reactive nitrogen species known to increase after ischemia/ reperfusion [11,12]. Peroxynitrite is generated by the nonenzymatic reaction between superoxide and nitric oxide and modifies proteins via several different mechanisms, including protein S-nitrosation and nitration of tyrosine residues.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Purified PDHC is highly sensitive to inactivation by exposure to hydroxyl radicals [5]. It is not known, however, whether inactivation occurs after exposure to other forms of oxidative stress, e.g., nitric oxide and peroxynitrite, that are generated at abnormally high levels shown to promote postischemic neuronal injury during ischemic reperfusion [9,10].Peroxynitrite (ONOO − ) is a reactive nitrogen species known to increase after ischemia/ reperfusion [11,12]. Peroxynitrite is generated by the nonenzymatic reaction between superoxide and nitric oxide and modifies proteins via several different mechanisms, including protein S-nitrosation and nitration of tyrosine residues.…”

mentioning

confidence: 99%

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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The pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of pyruvate and represents the sole bridge between anaerobic and aerobic cerebral energy metabolism. Previous studies demonstrating loss of PDHC enzyme activity and immunoreactivity during reperfusion after cerebral ischemia suggest that oxidative modifications are involved. This study tested the hypothesis that hyperoxic reperfusion exacerbates loss of PDHC enzyme activity, possibly due to tyrosine nitration or S-nitrosation. We used a clinically relevant canine ventricular fibrillation cardiac arrest model in which, after resuscitation and ventilation on either 100% O 2 (hyperoxic) or 21-30% O 2 (normoxic), animals were sacrificed at 2 h reperfusion and the brains removed for enzyme activity and immunoreactivity measurements. Animals resuscitated under hyperoxic conditions exhibited decreased PDHC activity and elevated 3-nitrotyrosine immunoreactivity in the hippocampus but not the cortex, compared to nonischemic controls. These measures were unchanged in normoxic animals. In vitro exposure of purified PDHC to peroxynitrite resulted in a dose-dependent loss of activity and increased nitrotyrosine immunoreactivity. These results support the hypothesis that oxidative stress contributes to loss of hippocampal PDHC activity during cerebral ischemia and reperfusion and suggest that PDHC is a target of peroxynitrite. KeywordsMitochondria; Hyperoxia; Nitrotyrosine; Normoxia; Oxidative stress; Global ischemia; Selective vulnerability; Free radicals Global cerebral ischemia and reperfusion cause severe neurochemical alterations, including oxidative modifications to lipids, proteins, and DNA. These and other covalent modifications can impair enzyme activities, including those necessary for energy metabolism. Alterations in these enzyme activities can limit postischemic aerobic metabolism and cellular ATP regeneration, thereby contributing to the pathophysiology of delayed neuronal cell death [1][2][3][4]. One enzyme known to be targeted and inactivated by reactive oxygen species is the pyruvate dehydrogenase complex (PDHC) [5]. Effects of ischemia/reperfusion on the PDHC can be particularly devastating because this enzyme forms the bridge between glycolysis and the Krebs cycle and can be the rate-limiting step in aerobic cerebral energy metabolism. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2008 October 21. Published in final edited form as:Free Radic Biol Med. 2006 June 1; 40(11): 1960-1970. doi:10.1016/j.freeradbiomed.2006.01.022. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe PDHC is located exclusively in the mitochondrial matrix and catalyzes the oxidative decarboxylation of pyruvate to form NADH and acetyl coenzyme A-the primary form of carbon that enters the Krebs cycle in the adult brain. Several laboratories have shown that PDHC enzyme activity is lost during cerebral ischemia/reperfusion [6][7][8]. PDHC im...

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“…Actually, asphyxiated brains often demonstrate apoptotic neuronal death (6). Additionally, it was recently found that in the early stage after hypoxic-ischemic (HI) insult, reactive oxygen species (ROS), such as nitric oxide and hydroxyl radicals, contribute to apoptotic neuronal death (7)(8)(9)(10)(11). ROS, which are induced by oxidative stress, are an important factor in initiating DNA peroxidation, which can directly trigger DNA fragmentation and thereby initiate apoptosis (12).…”

mentioning

confidence: 99%

Edaravone Inhibits DNA Peroxidation and Neuronal Cell Death in Neonatal Hypoxic-Ischemic Encephalopathy Model Rat

et al. 2009

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Neonatal hypoxic-ischemic encephalopathy (HIE) is the most frequent neurologic disease in the perinatal period. Its major cause is oxidative stress, which induces DNA peroxidation and apoptotic neuronal death. We examined 8-hydroxy-2Ј-deoxyguanosine (8-OHdG) expression to evaluate brain damage in neonatal HIE and the therapeutic effect of edaravone, a free radical scavenger. Using HPLC and immunohistochemistry, the 8-OHdG levels of neonatal HIE model Sprague-Dawley rats that were subjected to left common carotid artery ligation and 2-h hypoxia significantly increased after 24 -48 h of hypoxic-ischemic (HI) insult, but decreased after 72 h. Moreover, the number of apoptotic cells with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and karyorrhexis significantly increased after 24 -72 h of HI insult. In a therapeutic experiment, edaravone was administered i.p.

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Oxidants, antioxidants and the ischemic brain

Cited by 539 publications

References 156 publications

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Edaravone Inhibits DNA Peroxidation and Neuronal Cell Death in Neonatal Hypoxic-Ischemic Encephalopathy Model Rat

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