Postischemic inhibition of cerebral cortex pyruvate dehydrogenase

Bogaert, Yolanda E.; Rosenthal, Robert; Fiskum, Gary

doi:10.1016/0891-5849(94)90197-x

Cited by 129 publications

(118 citation statements)

References 30 publications

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“…The values for brain tissue maximal PDHC specific activity obtained in these experiments are within the range of previously published results for canine PDHC activity [5]. After 10 min global ischemia followed by 2 h reperfusion, animals that were ventilated under hyperoxic conditions exhibited approximately 37.5% less hippocampal homogenate PDHC activity (p < 0.05 one-way ANOVA; Tukey post hoc analysis), compared to sham-operated control animals or those resuscitated under normoxic conditions (Fig.…”

Section: Postischemic Hippocampal and Frontal Cortex Pdhc Enzyme Actisupporting

confidence: 88%

“…A similar reciprocal relationship between 3-nitrotyrosine immunoreactivity and PDHC enzymatic activity was observed with various periods of exposure to a constant concentration of SIN-1 (Fig. 5).Previous experiments demonstrated that the presence of certain PDHC substrates and cofactors protects against loss of enzymatic activity caused by exposure to the hydroxyl radical [5]. We therefore tested the ability of these molecules to protect against the loss of enzymatic activity observed after incubation with SIN-1.…”

supporting

confidence: 78%

“…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.…”

mentioning

confidence: 99%

“…One proposed mechanism of reperfusion-dependent enzyme inactivation involves the attack of free radicals on the enzyme complex. 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].…”

mentioning

confidence: 99%

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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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Section: Postischemic Hippocampal and Frontal Cortex Pdhc Enzyme Actisupporting

confidence: 88%

supporting

confidence: 78%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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“…However, the precise interaction of these restricting regimes with protein oxidation is unknown, and there are disparities (see [235]) that require clarification. Site-specific modifications of selected proteins have been observed [236], and could explain these disparities.…”

Section: Oxidized Proteins and Toxicity To The Host Organismmentioning

confidence: 99%

Biochemistry and pathology of radical-mediated protein oxidation

Dean

Stocker

et al. 1997

Biochemical Journal

1,551

982

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Radical-mediated damage to proteins may be initiated by electron leakage, metal-ion-dependent reactions and autoxidation of lipids and sugars. The consequent protein oxidation is O2-dependent, and involves several propagating radicals, notably alkoxyl radicals. Its products include several categories of reactive species, and a range of stable products whose chemistry is currently being elucidated. Among the reactive products, protein hydroperoxides can generate further radical fluxes on reaction with transition-metal ions; protein-bound reductants (notably dopa) can reduce transition-metal ions and thereby facilitate their reaction with hydroperoxides; and aldehydes may participate in Schiff-base formation and other reactions. Cells can detoxify some of the reactive species, e.g. by reducing protein hydroperoxides to unreactive hydroxides. Oxidized proteins are often functionally inactive and their unfolding is associated with enhanced susceptibility to proteinases. Thus cells can generally remove oxidized proteins by proteolysis. However, certain oxidized proteins are poorly handled by cells, and together with possible alterations in the rate of production of oxidized proteins, this may contribute to the observed accumulation and damaging actions of oxidized proteins during aging and in pathologies such as diabetes, atherosclerosis and neurodegenerative diseases. Protein oxidation may also sometimes play controlling roles in cellular remodelling and cell growth. Proteins are also key targets in defensive cytolysis and in inflammatory self-damage. The possibility of selective protection against protein oxidation (antioxidation) is raised.

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Oxidative Damage to Proteins: Structural Modifications and Consequences in Cell Function

Cabiscol

Ros

2006

Redox Proteomics

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Postischemic inhibition of cerebral cortex pyruvate dehydrogenase

Cited by 129 publications

References 30 publications

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Biochemistry and pathology of radical-mediated protein oxidation

Oxidative Damage to Proteins: Structural Modifications and Consequences in Cell Function

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