title: Argon protects against hypoxic-ischemic brain injury in neonatal rats through activation of nuclear factor (erythroid-derived 2)-like 2.
abstract: Perinatal hypoxic ischaemic encephalopathy (HIE) has a high mortality rate with neuropsychological impairment. This study investigated the neuroprotective effects of argon against neonatal hypoxic-ischaemic brain injury.In vitro cortical neuronal cell cultures derived from rat foetuses were subjected to an oxygen and glucose deprivation (OGD) challenge for 90 minutes and then exposed to 70% argon or nitrogen with 5% carbon dioxide and balanced with oxygen for 2 hours.In vivo, seven-day-old rats were subjected to unilateral common carotid artery ligation followed by hypoxic (8% oxygen balanced with nitrogen) insult for 90 minutes. They were exposed to 70% argon or nitrogen balanced with oxygen for 2 hours. In vitro, argon treatment of cortical neuronal cultures resulted in a significant increase of p-mTOR and Nuclear factor (erythroid-derived 2)-like 2(Nrf2) and protection against OGD challenge. Inhibition of m-TOR through Rapamycin or Nrf2 through siRNA abolished argon-mediated cyto-protection. In vivo, argon exposure significantly enhanced Nrf2 and its down-stream effector NAD(P)H Dehydrogenase, Quinone 1(NQO1) and superoxide dismutase 1(SOD1). Oxidative stress, neuroinflammation and neuronal cell death were significantly decreased and brain infarction was markedly reduced. Blocking PI-3K through wortmannin or ERK1/2 through U0126 attenuated argon-mediated neuroprotection.These data provide a new molecular mechanism for the potential application of Argon as a neuroprotectant in HIE.
authors.affiliation: Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Mitchell
authors.affiliation: Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ciechanowicz
authors.affiliation: Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
authors.forename: Sinead
authors.initials: S
authors.lastname: Savage
authors.affiliation: Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Tianlong
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Neurosugery, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
mesh_terms: D000818:Animals; D051381:Rats; D000831:Animals, Newborn; D001128:Argon / Q000494:pharmacology; D002478:Cells, Cultured; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
chemical_list: D001128:Argon; D018696:Neuroprotective Agents; D051267:NF-E2-Related Factor 2
keywords: Nrf2; argon; perinatal hypoxic-ischaemic encephalopathy