Reactive Oxygen Species-Mediated Inactivation of Pyruvate Dehydrogenase

Tabatabaie, Tahereh; Potts, Jamaica D.; Floyd, Robert A.

doi:10.1006/abbi.1996.0560

Cited by 76 publications

(61 citation statements)

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“…14 Previous studies have also shown that ROS mediates inactivation of PDH 11 and that the PDH complex is a target of oxidative stress. 34 It is likely that the up-regulation of PDH activity, which can be attributed to decreased ROS by ethanol, helps to preserve aerobic metabolism further enhanced by NBO.…”

Section: Strokementioning

confidence: 99%

“…Activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX), especially during reperfusion, also contributes to the generation of ROS. 10 ROS further impairs the expression of pyruvate dehydrogenase (PDH), 11 which serves as the critical link between glycolysis (anaerobic metabolism) and the tricarboxylic acid cycle by catalyzing the important transition step of pyruvate to acetyl coenzyme A. The down-regulation of PDH potentiates metabolic stress.…”

Section: Conclusion-combinationmentioning

confidence: 99%

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Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

et al. 2013

Stroke

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Background and Purpose— Normobaric oxygenation (NBO) and ethanol both provide neuroprotection in stroke. We evaluated the enhanced neuroprotective effect of combining these 2 treatments in a rat stroke model. Methods— Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 2 hours. Reperfusion was then established and followed by treatment with either (1) an intraperitoneal injection of ethanol (1.0 g/kg), (2) NBO treatment (2-hour duration), or (3) NBO plus ethanol. The extent of brain injury was determined by infarct volume and motor performance. Oxidative metabolism was determined by ADP/ATP ratios, reactive oxygen species levels, nicotinamide adenine dinucleotide phosphate oxidase activity, and pyruvate dehydrogenase activity. Protein expression of major nicotinamide adenine dinucleotide phosphate oxidase subunits (p47 phox , gp91 phox , and p67 phox ) and the enzyme pyruvate dehydrogenase was evaluated through Western immunoblotting. Results— NBO and ethanol monotherapies each demonstrated reductions as compared to stroke without treatment in infarct volume (36.7% and 37.9% vs 48.4%) and neurological deficits (score of 6.4 and 6.5 vs 8.4); however, the greatest neuroprotection (18.8% of infarct volume and 4.4 neurological deficit) was found in animals treated with combination therapy. This neuroprotection was associated with the largest reductions in ADP/ATP ratios, reactive oxygen species levels, and nicotinamide adenine dinucleotide phosphate oxidase activity, and the largest increase in pyruvate dehydrogenase activity. Conclusions— Combination therapy with NBO and ethanol enhances the neuroprotective effect produced by each therapy alone. The mechanism behind this synergistic action is related to changes in cellular metabolism after ischemia reperfusion. NBO plus ethanol is attractive for clinical study because of its ease of use, tolerability, and tremendous neuroprotective potential in stroke.

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Section: Strokementioning

confidence: 99%

Section: Conclusion-combinationmentioning

confidence: 99%

Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

et al. 2013

Stroke

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“…PDHC is a multienzyme complex composed of 6 subunits and 2 regulatory kinase molecules, PDK and PDP. 5 Any dysfunction of PDHC and its regulators would result in metabolic crisis, such as a decline in ATP and phosphocreatine, inability to generate nicotinamide adenine dinucleotide and accumulation of lactic acid. 5 Specifically, targeted regulation of PDHC occurs primarily via site-specific phosphorylation.…”

Section: Pdhc Mechanism In Ischemiamentioning

confidence: 99%

“…5 Any dysfunction of PDHC and its regulators would result in metabolic crisis, such as a decline in ATP and phosphocreatine, inability to generate nicotinamide adenine dinucleotide and accumulation of lactic acid. 5 Specifically, targeted regulation of PDHC occurs primarily via site-specific phosphorylation. 6 After ischemic stroke, a severe oxygen deprivation leads to a large impairment of oxidative phosphorylation, thus limiting the production of ATP.…”

Section: Pdhc Mechanism In Ischemiamentioning

confidence: 99%

“…It is composed of multiple subunits that altogether convert pyruvate to acetyl coenzyme A to eventually make ATP needed for different cellular functions. 5 PDHC's vast size and strict regulation makes it sensitive to inactivation and downregulation in stroke. Two key regulators of PDHC are pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP).…”

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confidence: 99%

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Ethanol and Normobaric Oxygen

Elmadhoun

Peng

et al. 2015

Stroke

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Background and Purpose-Ischemic stroke induces metabolic disarray. A central regulatory site, pyruvate dehydrogeanse complex (PDHC) sits at the cross-roads of 2 fundamental metabolic pathways: aerobic and anaerobic. In this study, we combined ethanol (EtOH) and normobaric oxygen (NBO) to develop a novel treatment to modulate PDHC and its regulatory proteins, namely pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase, leading to improved metabolism and reduced oxidative damage. Methods-Sprague-Dawley rats were subjected to transient (2, 3, or 4 hours) middle cerebral artery occlusion followed by 3-or 24-hour reperfusion, or permanent (28 hours) middle cerebral artery occlusion without reperfusion. At 2 hours after the onset of ischemia, rats received either an intraperitoneal injection of saline, 1 dose of EtOH (1.5 g/kg) for 2-and 3-hour middle cerebral artery occlusion, 2 doses of EtOH (1.5 g/kg followed by 1.0 g/kg in 2 hours) in 4 hours or permanent middle cerebral artery occlusion, and EtOH+95% NBO (at 2 hours after the onset of ischemia for 6 hours) in permanent stroke. Infarct volumes and neurological deficits were examined. Oxidative metabolism and stress were determined by measuring ADP/ATP ratio and reactive oxygen species levels. Protein levels of PDHC, pyruvate dehydrogenase kinase, and pyruvate dehydrogenase phosphatase were assessed. Results-EtOH induced dose-dependent neuroprotection in transient ischemia. Compared to EtOH or NBO alone,NBO+EtOH produced the best outcomes in permanent ischemia. These therapies improved brain oxidative metabolism by decreasing ADP/ATP ratios and reactive oxygen species levels, in association with significantly raised levels of PDHC and pyruvate dehydrogenase phosphatase, as well as decreased pyruvate dehydrogenase kinase. Key Words: EtOH ◼ ischemia-reperfusion injury ◼ metabolism ◼ pyruvate dehydrogeanse complex ◼ pyruvate dehydrogenase kinase ◼ pyruvate dehydrogenase phosphatase ◼ reactive oxygen species Conclusions-Both

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

Cabiscol

Ros

2006

Redox Proteomics

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Reactive Oxygen Species-Mediated Inactivation of Pyruvate Dehydrogenase

Cited by 76 publications

References 0 publications

Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

Ethanol and Normobaric Oxygen

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

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