Argon protects against hypoxic-ischemic brain injury in neonatal rats through activation of nuclear factor (erythroid-derived 2)-like 2

Hailin Zhao; Sian Mitchell; Sarah Ciechanowicz; Sinead Savage; Tianlong Wang; Xunming Ji; Daqing Ma

doi:10.18632/oncotarget.8241

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Research Papers:

Argon protects against hypoxic-ischemic brain injury in neonatal rats through activation of nuclear factor (erythroid-derived 2)-like 2

Hailin Zhao, Sian Mitchell, Sarah Ciechanowicz, Sinead Savage, Tianlong Wang, Xunming Ji and Daqing Ma _

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Oncotarget. 2016; 7:25640-25651. https://doi.org/10.18632/oncotarget.8241

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Abstract

Hailin Zhao1, Sian Mitchell1, Sarah Ciechanowicz1, Sinead Savage1, Tianlong Wang2, Xunming Ji3, Daqing Ma1

1Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK

2Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China

3Department of Neurosugery, Xuanwu Hospital, Capital Medical University, Beijing, China

Correspondence to:

Daqing Ma, email: [email protected]

Keywords: argon, perinatal hypoxic-ischaemic encephalopathy, Nrf2

Received: January 11, 2016 Accepted: March 07, 2016 Published: March 21, 2016

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.

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Research Papers:

Argon protects against hypoxic-ischemic brain injury in neonatal rats through activation of nuclear factor (erythroid-derived 2)-like 2

Abstract