Neuronal Transmembrane Chloride Transport Has a Time-Dependent Influence on Survival of Hippocampal Cultures to Oxygen-Glucose Deprivation
by
Ana-Maria Zagrean 1,*
, Ioana-Florentina Grigoras 1,2, Mara Ioana Iesanu 1, Rosana-Bristena Ionescu 1, Diana Maria Chitimus 1, Robert Mihai Haret 1, Bogdan Ianosi 1,3, Mihai Ceanga 1,4,* and Leon Zagrean 1
Ana-Maria Zagrean 1,*, Ioana-Florentina Grigoras 1,2, Mara Ioana Iesanu 1, Rosana-Bristena Ionescu 1, Diana Maria Chitimus 1, Robert Mihai Haret 1, Bogdan Ianosi 1,3, Mihai Ceanga 1,4,* and Leon Zagrean 1
1
Neuroscience Laboratory, Division of Physiology and Neuroscience, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
2
Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
3
Department of Neurology, Division of Neurocritical Care, Medical University of Innsbruck, Innsbruck 6020, Austria
4
Hans Berger Department of Neurology, Jena University Hospital, Jena 07747, Germany
*
Authors to whom correspondence should be addressed.
Brain Sci. 2019, 9(12), 360; https://doi.org/10.3390/brainsci9120360
Received: 16 November 2019 / Revised: 2 December 2019 / Accepted: 5 December 2019 / Published: 6 December 2019
(This article belongs to the Collection Collection on Molecular and Cellular Neuroscience)
Neuronal ischemia results in chloride gradient alterations which impact the excitatory–inhibitory balance, volume regulation, and neuronal survival. Thus, the Na+/K+/Cl− co-transporter (NKCC1), the K+/ Cl− co-transporter (KCC2), and the gamma-aminobutyric acid A (GABAA) receptor may represent therapeutic targets in stroke, but a time-dependent effect on neuronal viability could influence the outcome. We, therefore, successively blocked NKCC1, KCC2, and GABAA (with bumetanide, DIOA, and gabazine, respectively) or activated GABAA (with isoguvacine) either during or after oxygen-glucose deprivation (OGD). Primary hippocampal cultures were exposed to a 2-h OGD or sham normoxia treatment, and viability was determined using the resazurin assay. Neuronal viability was significantly reduced after OGD, and was further decreased by DIOA treatment applied during OGD (p < 0.01) and by gabazine applied after OGD (p < 0.05). Bumetanide treatment during OGD increased viability (p < 0.05), while isoguvacine applied either during or after OGD did not influence viability. Our data suggests that NKCC1 and KCC2 function has an important impact on neuronal viability during the acute ischemic episode, while the GABAA receptor plays a role during the subsequent recovery period. These findings suggest that pharmacological modulation of transmembrane chloride transport could be a promising approach during stroke and highlight the importance of the timing of treatment application in relation to ischemia-reoxygenation.
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Keywords:
oxygen-glucose deprivation; hippocampal culture; NKCC1; KCC2; GABAA; stroke
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MDPI and ACS Style
Zagrean, A.-M.; Grigoras, I.-F.; Iesanu, M.I.; Ionescu, R.-B.; Chitimus, D.M.; Haret, R.M.; Ianosi, B.; Ceanga, M.; Zagrean, L. Neuronal Transmembrane Chloride Transport Has a Time-Dependent Influence on Survival of Hippocampal Cultures to Oxygen-Glucose Deprivation. Brain Sci. 2019, 9, 360.
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