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

Xu, Geng; Fu, Paul; Ji, Xunming; Peng, Changya; Fredrickson, Vance L; Sy, Christopher; Wang, Mengqi; Li, Feng; Du, Hongguang; Tan, Xiaomu; Hüttemann, Maik; Guthikonda, Murali; Ding, Yuchuan

doi:10.1161/strokeaha.111.000315

Cited by 45 publications

(33 citation statements)

References 46 publications

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“…This, in turn, raises the production of ROS after reperfusion which exacerbates cell and tissue injuries. 17,27 Our present results support previous study, 5 where large increase in ADP/ATP ratio led to significant rise in ROS production, which in turn exacerbates impairment of PDHC expression. Other studies have shown that PDHC deficiency is related to decreased activity of critical enzymes required for free radical removal, such as MnSOD.…”

Section: Pdhc Mechanism In Ischemiasupporting

confidence: 91%

“…Because reperfusion therapy within a clinically realistic time window is not available to most patients with stroke, a goal of the study was to assess EtOH and NBO neuroprotection under severe ischemic conditions with longer time frames, in contrast to those used in a previous study with moderate stroke (2-hour occlusion or less) and shorter therapeutic window. 9,17 Our analysis after treatment with EtOH alone in transient ischemia or NBO+EtOH with permanent ischemia improved ATP production and reduced ROS generation. Although the measures here cannot definitely explain the better outcomes, our findings support a role of EtOH in stabilizing dysfunctional metabolic pathways mediated by PDHC, PDK, and PDP in ischemia.…”

Section: Discussion Etoh Nbo and Neuroprotectionmentioning

confidence: 92%

“…To maintain oxygen concentration, an oxygen controller (PRO-OX110; Reming Bioinstruments Co, Redfield, NY) was used and the oxygen flow rate was 2 L/min. 17 In addition, carbon dioxide was removed by placing a container of soda lime (Sigma) at the bottom of the chamber.…”

Section: Nbo Treatmentmentioning

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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Section: Pdhc Mechanism In Ischemiasupporting

confidence: 91%

Section: Discussion Etoh Nbo and Neuroprotectionmentioning

confidence: 92%

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Ethanol and Normobaric Oxygen

Elmadhoun

Peng

et al. 2015

Stroke

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“…The ROS method, as described previously by us (Geng et al, 2013), tests for H 2 O 2 with hydrogen peroxidase linked to a fluorescent compound. This is a reliable method for superoxide determination, as it assesses the enzymatic dismutation of superoxide into H 2 O 2 .…”

Section: Methodsmentioning

confidence: 99%

Exacerbation of Brain Injury by Post-Stroke Exercise Is Contingent Upon Exercise Initiation Timing

Khan

et al. 2017

Front. Cell. Neurosci.

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Accumulating evidence has demonstrated that post-stroke physical rehabilitation may reduce morbidity. The effectiveness of post-stroke exercise, however, appears to be contingent upon exercise initiation. This study assessed the hypothesis that very early exercise exacerbates brain injury, induces reactive oxygen species (ROS) generation, and promotes energy failure. A total of 230 adult male Sprague-Dawley rats were subjected to middle cerebral artery (MCA) occlusion for 2 h, and randomized into eight groups, including two sham injury control groups, three non-exercise and three exercise groups. Exercise was initiated after 6 h, 24 h and 3 days of reperfusion. Twenty-four hours after completion of exercise (and at corresponding time points in non-exercise controls), infarct volumes and apoptotic cell death were examined. Early brain oxidative metabolism was quantified by examining ROS, ATP and NADH levels 0.5 h after completion of exercise. Furthermore, protein expressions of angiogenic growth factors were measured in order to determine whether post-stroke angiogenesis played a role in rehabilitation. As expected, ischemic stroke resulted in brain infarction, apoptotic cell death and ROS generation, and diminished NADH and ATP production. Infarct volumes and apoptotic cell death were enhanced (p < 0.05) by exercise that was initiated after 6 h of reperfusion, but decreased by late exercise (24 h, 3 days). This exacerbated brain injury at 6 h was associated with increased ROS levels (p < 0.05), and decreased (p < 0.05) NADH and ATP levels. In conclusion, very early exercise aggravated brain damage, and early exercise-induced energy failure with ROS generation may underlie the exacerbation of brain injury. These results shed light on the manner in which exercise initiation timing may affect post-stroke rehabilitation.

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“…Increased formation of reactive oxygen (ROS) and nitrogen (RNS) species leads to changes in intracellular redox state and modulation of cell signaling pathways, resulting in alterations in gene expression. Data from both experimental and clinical studies suggest that beneficial effects of NBO or HBO treatment on brain or heart could be due to increased expression of antioxidant, anti-inflammatory, and anti-apoptotic proteins and reduced production of pro-oxidant, pro-inflammatory pro-apoptotic proteins [ [13][14][15], for review see [2]. However, this is in contrast with studies, which showed that hyperoxia increases cellular oxidative damage [16], for review see [11].…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of mitochondrial proteins in the guinea pig heart following long-term normobaric hyperoxia

et al. 2017

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Normobaric hyperoxia is applied for the treatment of a wide variety of diseases and clinical conditions related to ischemia or hypoxia, but it can increase the risk of tissue damage and its efficiency is controversial. In the present study, we analyzed cardiac mitochondrial proteome derived from guinea pigs after 60 h exposure to 100% molecular oxygen (NBO) or O enriched with oxygen cation (NBO+). Two-dimensional gel electrophoresis followed by MALDI-TOF/TOF mass spectrometry identified twenty-two different proteins (among them ten nonmitochondrial) that were overexpressed in NBO and/or NBO+ group. Identified proteins were mainly involved in cellular energy metabolism (tricarboxylic acid cycle, oxidative phosphorylation, glycolysis), cardioprotection against stress, control of mitochondrial function, muscle contraction, and oxygen transport. These findings support the viewpoint that hyperoxia is associated with cellular stress and suggest complex adaptive responses which probably contribute to maintain or improve intracellular ATP levels and contractile function of cardiomyocytes. In addition, the results suggest that hyperoxia-induced cellular stress may be partially attenuated by utilization of NBO+ treatment.

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

Cited by 45 publications

References 46 publications

Ethanol and Normobaric Oxygen

Ethanol and Normobaric Oxygen

Exacerbation of Brain Injury by Post-Stroke Exercise Is Contingent Upon Exercise Initiation Timing

Proteomic analysis of mitochondrial proteins in the guinea pig heart following long-term normobaric hyperoxia

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