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Sustained Na(+)/H(+) Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation
Hypoxia ischemia (HI)-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not ful...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879304/ https://www.ncbi.nlm.nih.gov/pubmed/24392123 http://dx.doi.org/10.1371/journal.pone.0084294 |
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author | Cengiz, Pelin Kintner, Douglas B. Chanana, Vishal Yuan, Hui Akture, Erinc Kendigelen, Pinar Begum, Gulnaz Fidan, Emin Uluc, Kutluay Ferrazzano, Peter Sun, Dandan |
author_facet | Cengiz, Pelin Kintner, Douglas B. Chanana, Vishal Yuan, Hui Akture, Erinc Kendigelen, Pinar Begum, Gulnaz Fidan, Emin Uluc, Kutluay Ferrazzano, Peter Sun, Dandan |
author_sort | Cengiz, Pelin |
collection | PubMed |
description | Hypoxia ischemia (HI)-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not fully understood. In the current study, we investigated the role of Na(+)/H(+) exchanger isoform 1 (NHE1) protein in mouse reactive hippocampal astrocyte function in an in vitro ischemia model (oxygen/glucose deprivation and reoxygenation, OGD/REOX). 2 h OGD significantly increased NHE1 protein expression and NHE1-mediated H(+) efflux in hippocampal astrocytes. NHE1 activity remained stimulated during 1–5 h REOX and returned to the basal level at 24 h REOX. NHE1 activation in hippocampal astrocytes resulted in intracellular Na(+) and Ca(2+) overload. The latter was mediated by reversal of Na(+)/Ca(2+) exchange. Hippocampal astrocytes also exhibited a robust release of gliotransmitters (glutamate and pro-inflammatory cytokines IL-6 and TNFα) during 1–24 h REOX. Interestingly, inhibition of NHE1 activity with its potent inhibitor HOE 642 not only reduced Na(+) overload but also gliotransmitter release from hippocampal astrocytes. The noncompetitive excitatory amino acid transporter inhibitor TBOA showed a similar effect on blocking the glutamate release. Taken together, we concluded that NHE1 plays an essential role in maintaining H(+) homeostasis in hippocampal astrocytes. Over-stimulation of NHE1 activity following in vitro ischemia disrupts Na(+) and Ca(2+) homeostasis, which reduces Na(+)-dependent glutamate uptake and promotes release of glutamate and cytokines from reactive astrocytes. Therefore, blocking sustained NHE1 activation in reactive astrocytes may provide neuroprotection following HI. |
format | Online Article Text |
id | pubmed-3879304 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38793042014-01-03 Sustained Na(+)/H(+) Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation Cengiz, Pelin Kintner, Douglas B. Chanana, Vishal Yuan, Hui Akture, Erinc Kendigelen, Pinar Begum, Gulnaz Fidan, Emin Uluc, Kutluay Ferrazzano, Peter Sun, Dandan PLoS One Research Article Hypoxia ischemia (HI)-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not fully understood. In the current study, we investigated the role of Na(+)/H(+) exchanger isoform 1 (NHE1) protein in mouse reactive hippocampal astrocyte function in an in vitro ischemia model (oxygen/glucose deprivation and reoxygenation, OGD/REOX). 2 h OGD significantly increased NHE1 protein expression and NHE1-mediated H(+) efflux in hippocampal astrocytes. NHE1 activity remained stimulated during 1–5 h REOX and returned to the basal level at 24 h REOX. NHE1 activation in hippocampal astrocytes resulted in intracellular Na(+) and Ca(2+) overload. The latter was mediated by reversal of Na(+)/Ca(2+) exchange. Hippocampal astrocytes also exhibited a robust release of gliotransmitters (glutamate and pro-inflammatory cytokines IL-6 and TNFα) during 1–24 h REOX. Interestingly, inhibition of NHE1 activity with its potent inhibitor HOE 642 not only reduced Na(+) overload but also gliotransmitter release from hippocampal astrocytes. The noncompetitive excitatory amino acid transporter inhibitor TBOA showed a similar effect on blocking the glutamate release. Taken together, we concluded that NHE1 plays an essential role in maintaining H(+) homeostasis in hippocampal astrocytes. Over-stimulation of NHE1 activity following in vitro ischemia disrupts Na(+) and Ca(2+) homeostasis, which reduces Na(+)-dependent glutamate uptake and promotes release of glutamate and cytokines from reactive astrocytes. Therefore, blocking sustained NHE1 activation in reactive astrocytes may provide neuroprotection following HI. Public Library of Science 2014-01-02 /pmc/articles/PMC3879304/ /pubmed/24392123 http://dx.doi.org/10.1371/journal.pone.0084294 Text en © 2014 Cengiz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Cengiz, Pelin Kintner, Douglas B. Chanana, Vishal Yuan, Hui Akture, Erinc Kendigelen, Pinar Begum, Gulnaz Fidan, Emin Uluc, Kutluay Ferrazzano, Peter Sun, Dandan Sustained Na(+)/H(+) Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation |
title | Sustained Na(+)/H(+) Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation |
title_full | Sustained Na(+)/H(+) Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation |
title_fullStr | Sustained Na(+)/H(+) Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation |
title_full_unstemmed | Sustained Na(+)/H(+) Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation |
title_short | Sustained Na(+)/H(+) Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation |
title_sort | sustained na(+)/h(+) exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879304/ https://www.ncbi.nlm.nih.gov/pubmed/24392123 http://dx.doi.org/10.1371/journal.pone.0084294 |
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