title: Synergetic neuroprotection of normobaric oxygenation and ethanol in ischemic stroke through improved oxidative mechanism.
abstract: OBJECTIVE
  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.
authors.affiliation: Cerebral Vascular Diseases Research Institute (China-America Institute of Neuroscience), Capital Medical University, Beijing, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Geng
authors.forename: Paul
authors.initials: P
authors.lastname: Fu
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.forename: Changya
authors.initials: C
authors.lastname: Peng
authors.forename: Vance
authors.initials: V
authors.lastname: Fredrickson
authors.forename: Christopher
authors.initials: C
authors.lastname: Sy
authors.forename: Ran
authors.initials: R
authors.lastname: Meng
authors.forename: Feng
authors.initials: F
authors.lastname: Ling
authors.forename: Huishan
authors.initials: H
authors.lastname: Du
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Tan
authors.forename: Maik
authors.initials: M
authors.lastname: Hüttemann
authors.forename: Murali
authors.initials: M
authors.lastname: Guthikonda
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010102:Oxygen Inhalation Therapy / Q000379:methods*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D000431:Ethanol; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate