title: Heme Oxygenase-1 Mediates Neuroprotection Conferred by Argon in Combination with Hypothermia in Neonatal Hypoxia-Ischemia Brain Injury.
abstract: Hypoxic-ischemic encephalopathy is a major cause of mortality and disability in the newborn. The authors investigated the protective effects of argon combined with hypothermia on neonatal rat hypoxic-ischemic brain injury.
  
  
  
  In in vitro studies, rat cortical neuronal cell cultures were challenged by oxygen and glucose deprivation for 90 min and exposed to 70% Ar or N2 with 5% CO2 balanced with O2, at 33°C for 2 h. Neuronal phospho-Akt, heme oxygenase-1 and phospho-glycogen synthase kinase-3β expression, and cell death were assessed. In in vivo studies, neonatal rats were subjected to unilateral common carotid artery ligation followed by hypoxia (8% O2 balanced with N2 and CO2) for 90 min. They were exposed to 70% Ar or N2 balanced with oxygen at 33°, 35°, and 37°C for 2 h. Brain injury was assessed at 24 h or 4 weeks after treatment.
  
  
  
  In in vitro studies, argon-hypothermia treatment increased phospho-Akt and heme oxygenase-1 expression and significantly reduced the phospho-glycogen synthase kinase-3β Tyr-216 expression, cytochrome C release, and cell death in oxygen-glucose deprivation-exposed cortical neurons. In in vivo studies, argon-hypothermia treatment decreased hypoxia/ischemia-induced brain infarct size (n = 10) and both caspase-3 and nuclear factor-κB activation in the cortex and hippocampus. It also reduced hippocampal astrocyte activation and proliferation. Inhibition of phosphoinositide-3-kinase (PI3K)/Akt pathway through LY294002 attenuated cerebral protection conferred by argon-hypothermia treatment (n = 8).
  
  
  
  Argon combined with hypothermia provides neuroprotection against cerebral hypoxia-ischemia damage in neonatal rats, which could serve as a new therapeutic strategy against hypoxic-ischemic encephalopathy.
authors.affiliation: From the Faculty of Medicine, Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom (H.Z., S.M., S.K., Y.T.C., M.T., D.M.); Department of Anesthesiology, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China (Q.L.); Division of Imaging Sciences and Biomedical Engineering, Centre for the Developing Brain, King's College London, St. Thomas' Hospital, London, United Kingdom (H.H.); Perinatal Center, Institute of Physiology and Neurosciences and Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (H.H.); and Reproductive Biology, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom (M.R.J.).
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhao
authors.forename: Sian
authors.initials: S
authors.lastname: Mitchell
authors.forename: Stefania
authors.initials: S
authors.lastname: Koumpa
authors.forename: Yushi Tracy
authors.initials: YT
authors.lastname: Cui
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Lian
authors.forename: Henrik
authors.initials: H
authors.lastname: Hagberg
authors.forename: Mark R
authors.initials: MR
authors.lastname: Johnson
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001128:Argon / Q000494:pharmacology* / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000628:therapy*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018696:Neuroprotective Agents; D001128:Argon; D045304:Cytochromes c; D051547:Heme Oxygenase-1; D038362:Glycogen Synthase Kinase 3