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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00344

Hypoxic Preconditioning Maintains GLT-1 against Transient Global Cerebral Ischemia through Upregulating Cx43 and Inhibiting c-Src

  • 1Institute of Neurosciences and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University and Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Second Affiliated Hospital of Guangzhou Medical University, China
  • 2Department of Environmental Health Sciences, Rollins School of Public Health, Emory University, United States
  • 3Department of Neurology, First Affiliated Hospital of Guangxi Medical University, China

Transient global cerebral ischemia (tGCI) causes excessive release of glutamate from neurons. Astrocytic glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) together play a predominant role in maintaining glutamate at normal extracellular concentrations. Though our previous studies reported the alleviation of tGCI-induced neuronal death by hypoxic preconditioning (HPC) in hippocampal CA1 of adult rats, the underlying mechanism has not yet been fully elaborated. In this study, we aimed to investigate the roles of GLT-l and GS in the neuroprotection mediated by HPC against tGCI and to ascertain whether these roles can be regulated by connexin 43 (Cx43) and c-Src activity. We found that HPC decreased the level of extracellular glutamate in CA1 after tGCI via maintenance of GLT-1 expression and GS activity. Inhibition of GLT-1 expression with dihydrokainate (DHK) or inhibition of GS activity with methionine sulfoximine (MSO) abolished the neuroprotection induced by HPC. Also, HPC markedly upregulated Cx43 and inhibited p-c-Src expression in CA1 after tGCI, whereas inhibition of Cx43 with Gap26 dramatically reversed this effect. Furthermore, inhibition of p-c-Src with 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3, 4-d) pyrimidine (PP2) decreased c-Src activity, increased protein levels of GLT-1 and Cx43, enhanced GS activity, and thus reduced extracellular glutamate level in CA1 after tGCI. Collectively, our data demonstrated that reduced extracellular glutamate induced by HPC against tGCI through preventing the reduction of GLT-1 expression and maintaining GS activity in hippocampal CA1, which was mediated by upregulating Cx43 expression and inhibiting c-Src activity.

Keywords: Glutamate transporter 1, glutamine synthetase, Connexin 43, c-src, cerebral ischemia, hypoxic preconditioning, Neuroprotection.

Received: 08 Jan 2018; Accepted: 03 Sep 2018.

Edited by:

Tibor Harkany, Karolinska Institutet (KI), Sweden

Reviewed by:

Luca Peruzzotti-Jametti, University of Cambridge, United Kingdom
De-Pei Li, University of Texas MD Anderson Cancer Center, United States  

Copyright: © 2018 Li, Zhou, Zhan, Shi, Sun, Liu, Liu, Liang, Tan, Xu and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. En Xu, Second Affiliated Hospital of Guangzhou Medical University, Institute of Neurosciences and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University and Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, 510260, Guangdong, China, enxu@163.net