Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Rosenthal

et al. 2007

Stroke

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146

Background and Purpose-Previous reports indicate that compared with normoxia, 100% ventilatory O 2 during early reperfusion after global cerebral ischemia decreases hippocampal pyruvate dehydrogenase activity and increases neuronal death. However, current standards of care after cardiac arrest encourage the use of 100% O 2 during resuscitation and for an undefined period thereafter. Using a clinically relevant canine cardiac arrest model, in this study we tested the hypothesis that hyperoxic reperfusion decreases hippocampal glucose metabolism and glutamate synthesis. Methods-After 10 minutes of cardiac arrest, animals were resuscitated and ventilated for 1 hour with 100% O 2 (hyperoxic) or 21% to 30% O 2 (normoxic). At 30 minutes reperfusion, [1-13 C]glucose was infused, and at 2 hours, brains were rapidly removed and frozen. Extracted metabolites were analyzed by 13 C nuclear magnetic resonance spectroscopy. Results-Compared with nonischemic controls, the hippocampi from hyperoxic animals had elevated levels of unmetabolized 13 C-glucose and decreased incorporation of 13 C into all isotope isomers of glutamate. These findings indicate impaired neuronal metabolism via the pyruvate dehydrogenase pathway for carbon entry into the tricarboxylic acid cycle and impaired glucose metabolism via the astrocytic pyruvate carboxylase pathway. No differences were observed in the cortex, indicating that the hippocampus is more vulnerable to metabolic changes induced by hyperoxic reperfusion. Conclusions-These results represent the first direct evidence that hyperoxia after cardiac arrest impairs hippocampal oxidative energy metabolism in the brain and challenge the rationale for using excessively high resuscitative ventilatory O 2 .

Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 65%

mentioning

confidence: 99%

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Hyperoxic Reperfusion After Global Ischemia Decreases Hippocampal Energy Metabolism

Richards

Rosenthal

et al. 2007

Stroke

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146

“…Several studies have demonstrated that when animals are hyperoxic during reperfusion following global cerebral ischemia, brain tissue oxidative stress markers, impaired cerebral energy metabolism, neuronal death, and neurologic impairment are greater than what is observed following normoxic reperfusion (Balan et al, 2006;Liu et al, 1998;Mickel et al, 1987;Richards et al, 2006;Vereczki et al, 2006). These findings have led to the concept that brain tissue oxygenation in excess of what is necessary to saturate metabolic O 2 utilization is toxic during early reperfusion, when altered intracellular conditions, e.g., pH, [Ca 2+ ], etc., may either promote the formation of reactive oxygen species (ROS) or inhibit their detoxification (Rosenthal and Fiskum, 2005).…”

Section: Introductionmentioning

confidence: 99%

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Danilov

2008

Glia

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Astrocyte dysfunction and death accompany cerebral ischemia/reperfusion and possibly compromise neuronal survival. Animal studies indicate that neuronal death, neurologic injury, and oxidative molecular modifications are worse in animals exposed to hyperoxic compared to normoxic ventilation during reperfusion after global cerebral ischemia. It is unknown, however, whether ambient O 2 affects brain cell survival using in vitro ischemia paradigms where mechanisms of injury to specific cell types can be more thoroughly investigated. This study tested the hypothesis that compared with the supraphysiological level of 20% O 2 normally used in cell culture, lower, more physiological O 2 levels protect astrocytes from death following oxygen and glucose deprivation. Primary rat cortical astrocytes were cultured under either 7 or 20% O 2 , exposed to O 2 , and glucose deprivation for 4 h, and then exposed to normal medium under either 7 or 20% O 2 . Cell death and 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine immunoreactivities were assessed at different periods of reoxygenation. Astrocytes exposed to low levels of O 2 during reoxygenation undergo less death and exhibit lower levels of protein nitration and nucleic acid oxidation when compared with those under high levels of O 2 during reoxygenation. These results support the hypothesis that the 20% O 2 normally used in cell culture exacerbates astrocyte death and oxidative stress in an in vitro ischemia/reperfusion model compared to levels that more closely approximate those that exist in vivo.

“…The most acute influence of ROS/RNS on mitochondria is mediated by oxidative modifications of proteins present in the electron transport chain (ETC) [1,2], other metabolic proteins, e.g., pyruvate dehydrogenase aconitase and α-ketogluatarate dehydrogenase [3][4][5], and the inner membrane permeability transition pore (PTP) [6,7]. Oxidation of cardiolipin, a phospholipid primarily lo-…”

Section: Abstract Oxidative Stress and Loss Of Cellular Camentioning

confidence: 99%

Neuroprotection through Stimulation of Mitochondrial Antioxidant Protein Expression

Greco

2010

JAD

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Abstract. Oxidative stress and loss of cellular Ca2+ homeostasis are closely linked and are common denominators in the pathophysiology of many neurodegenerative diseases and acute disorders of the nervous system. Mitochondria are major targets of oxidative stress and abnormal intracellular Ca 2+ , as both can cause bioenergetic failure through synergistic activation of the mitochondrial inner membrane permeability transition pore. Opening of this molecularly ill-defined pore causes both collapse of the membrane potential, which drives oxidative phosphorylation, and release of small metabolites, including pyridine nucleotides and glutathione, which are necessary for energy metabolism and defense against oxidative stress. Expression of genes coding for many antioxidant defense proteins is regulated by the Nrf2 transcriptional activating factor. Translocation of this protein from the cytosol to the nucleus is stimulated by oxidative stress and by specific agents that either react with cysteine sulfhydryl groups present on the protein KEAP1, that normally binds and restricts Nrf2 translocation, or that stimulate serine phosphorylation of Nrf2. Recent evidence indicates that mitochondria are a target of the cytoprotective gene expression induced by Nrf2 and that this pathway can increase resistance to redox-regulated opening of the permeability transition pore. Pharmacologic stimulation of the Nrf2 system and its protection against mitochondrial bioenergetic dysfunction may therefore constitute a powerful mechanism for both pre-conditioning against neurodegeneration and for post-conditioning against neural cell death associated with acute neurologic injury.Keywords: Antioxidant, bioenergetics, calcium, cerebral ischemia, neurodegeneration, Nrf2, oxidative stress, permeability transition pore are located at mitochondria or that are extramitochondrial but have strong secondary effects on mitochondrial bioenergetic or apoptotic activities. The most acute influence of ROS/RNS on mitochondria is mediated by oxidative modifications of proteins present in the electron transport chain (ETC) [1,2], other metabolic proteins, e.g., pyruvate dehydrogenase aconitase and α-ketogluatarate dehydrogenase [3][4][5], and the inner membrane permeability transition pore (PTP) [6,7]. Oxidation of cardiolipin, a phospholipid primarily lo- OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION IN NEURODEGENERATION