title: Ethanol and normobaric oxygen: novel approach in modulating pyruvate dehydrogenase complex after severe transient and permanent ischemic stroke.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Both EtOH and EtOH+NBO treatments conferred neuroprotection in severe stroke by affecting brain metabolism. The treatment may modulate the damaging cascade of metabolic events by bringing the PDHC activity back to normal metabolic levels.
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.).
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Geng
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.).
authors.forename: Omar
authors.initials: O
authors.lastname: Elmadhoun
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.).
authors.forename: Changya
authors.initials: C
authors.lastname: Peng
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.). yding@med.wayne.edu jixm@ccmu.edu.cn.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.).
authors.forename: Adam
authors.initials: A
authors.lastname: Hafeez
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.).
authors.forename: Zongjian
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.).
authors.forename: Huishan
authors.initials: H
authors.lastname: Du
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.).
authors.forename: Jose A
authors.initials: JA
authors.lastname: Rafols
authors.affiliation: From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.). yding@med.wayne.edu jixm@ccmu.edu.cn.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000818:Animals; D000431:Ethanol / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000201:enzymology / Q000628:therapy*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010102:Oxygen Inhalation Therapy / Q000379:methods*; D011768:Pyruvate Dehydrogenase Complex / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D020521:Stroke / Q000201:enzymology / Q000628:therapy*
chemical_list: D018696:Neuroprotective Agents; D011768:Pyruvate Dehydrogenase Complex; D000431:Ethanol
keywords: EtOH; ischemia–reperfusion injury; metabolism; pyruvate dehydrogeanse complex; pyruvate dehydrogenase kinase; pyruvate dehydrogenase phosphatase; reactive oxygen species