title: Adjuvant therapies using normobaric oxygen with hypothermia or ethanol for reducing hyperglycolysis in thromboembolic cerebral ischemia.
abstract: OBJECTIVE
  Normobaric oxygen (NBO), ethanol (EtOH), and therapeutic hypothermia (TH) delivered alone or in combination have neuroprotective properties after acute stroke. We used an autologous thromboembolic rat stroke model to assess the additive effects of these treatments for reducing the deleterious effects of hyperglycolysis post-stroke in which reperfusion is induced with recombinant tissue plasminogen activator (rt-PA).
  
  
  METHODS
  Sprague-Dawley rats were subjected to middle cerebral artery (MCA) occlusion with an autologous embolus. One hour after occlusion, rt-PA was administered alone or with NBO (60%), EtOH (1.0 g/kg), TH (33 °C), either singly or in combination. Infarct volume and neurological deficit were assessed at 24h after rt-PA-induced reperfusion with or without other treatments. The extent of hyperglycolysis, as determined by cerebral glucose and lactate levels was evaluated at 3 and 24h after rt-PA administration. At the same time points, expressions of glucose transporter 1 (Glut1), glucose transporter 3 (Glut3), phosphofructokinase1 (PFK-1), and lactate dehydrogenase were (LDH) measured by Western blotting.
  
  
  RESULTS
  Following rt-PA in rats with thromboembolic stroke, NBO combined with TH or EtOH most effectively decreased infarct volume and neurological deficit. As compared to rt-PA alone, EtOH or TH but not NBO monotherapies significantly reduced post-stroke hyperglycolysis. The increased utilization of glucose and production of lactate post-stroke was prevented most effectively when NBO was combined with either EtOH or TH after reperfusion with rt-PA, as shown by the significantly decreased Glut1, Glut3, PFK-1, and LDH levels.
  
  
  CONCLUSIONS
  In a rat thromboembolic stroke model, both EtOH and TH used individually offer neuroprotection after the administration of rt-PA. While NBO monotherapy does not appear to be effective, it significantly potentiates the efficacy of EtOH and TH. The similar neuroprotection and underlying mechanisms pertaining to the attenuation of hyperglycolysis provided by EtOH or TH in combination with NBO suggest a possibility of substituting EtOH for TH. Thus a combination of NBO and EtOH, which are widely available and easily used, could become a novel and effective neuroprotective strategy in the clinical setting.
authors.affiliation: China-America Institute of Neuroscience, Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China; Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Stevenson
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: C
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA; Department of Radiology, Luhe Hospital, Capital Medical University, Beijing, China.
authors.forename: R
authors.initials: R
authors.lastname: Xin
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rastogi
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: K
authors.initials: K
authors.lastname: Liu
authors.affiliation: China-America Institute of Neuroscience, Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China; Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: X
authors.initials: X
authors.lastname: Geng
authors.affiliation: Cerebral Vascular Diseases Research Institute, Capital Medical University, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Cerebral Vascular Diseases Research Institute, Capital Medical University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Rafols
authors.affiliation: China-America Institute of Neuroscience, Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China. Electronic address: jizhili@medmail.com.cn.
authors.forename: Z
authors.initials: Z
authors.lastname: Ji
authors.affiliation: China-America Institute of Neuroscience, Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China; Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: yding@med.wayne.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D007035:Hypothermia / Q000188:drug therapy*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D000431:Ethanol; D010959:Tissue Plasminogen Activator; D010100:Oxygen
keywords: autologous embolus; combination therapy; glucose metabolism; ischemia/reperfusion injury; rt-PA