Sustained Na⁺/H⁺ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation

Cengiz, P and Kintner, DB and Chanana, V and Yuan, H and Akture, E and Kendigelen, P and Begum, G and Fidan, E and Uluc, K and Ferrazzano, P and Sun, D (2014) Sustained Na⁺/H⁺ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation. PLoS ONE, 9 (1).

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Abstract

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 Ca2+ overload. The latter was mediated by reversal of Na+/Ca2+ 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 Ca2+ 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. © 2014 Cengiz et al.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Cengiz, P Kintner, DB Chanana, V Yuan, H Akture, E Kendigelen, P Begum, G gub6@pitt.edu GUB6 Fidan, E Uluc, K Ferrazzano, P Sun, D dds30@pitt.edu DDS30
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Borlongan, Cesar V. UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	2 January 2014
Date Type:	Publication
Journal or Publication Title:	PLoS ONE
Volume:	9
Number:	1
DOI or Unique Handle:	10.1371/journal.pone.0084294
Schools and Programs:	School of Medicine > Neurology
Refereed:	Yes
Date Deposited:	16 Jun 2014 16:28
Last Modified:	22 Jun 2021 13:56
URI:	http://d-scholarship.pitt.edu/id/eprint/21866

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