Abstract
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.
Highlights
Stroke is the second leading cause of mortality worldwide, with an annual 5.5 million death toll [1].the incidence of stroke in young adults (18–50 years) has significantly increased in the past decade, with considerable socioeconomic impact because of high health-care costs and loss of labor productivity [2]
We aimed to examine the effect of specific blocking of NKCC1 [26], KCC2 (R(+)-[(dihydroindenyl)oxy] alkanoic acid—DIOA) [27], and gamma-aminobutyric acid A (GABAA) receptor
In this study we explored the effect of pharmacologically blocking chloride membrane transport via the NKCC1 and KCC2 co-transporters and the effect of GABAA receptor inhibition or activation on via the NKCC1 and KCC2 co-transporters and the effect of GABAA receptor inhibition or activation post-ischemic neuronal viability, when applied either during oxygen-glucose deprivation (OGD) or post-exposure
Summary
Stroke is the second leading cause of mortality worldwide, with an annual 5.5 million death toll [1].the incidence of stroke in young adults (18–50 years) has significantly increased in the past decade, with considerable socioeconomic impact because of high health-care costs and loss of labor productivity [2]. Clinical practice reveals a preclinical setting, during which cerebral ischemia continues, and for which there is currently no approved treatment, as well as a clinical therapeutic window during which revascularization may be attempted. Present guidelines recommend pharmacological or interventional revascularization strategies, which are limited by a time window and have a non-insignificant degree of treatment failure or complication rate [3,4,5]. Patients often receive pharmacological treatments for sedation (e.g., during transport in the preclinical phase, when undergoing interventional procedures, or during intensive care treatment) or for increased intracranial pressure (e.g., after a malignant stroke or intracerebral hemorrhage), which involve modulation of gamma-aminobutyric acid A (GABAA ) receptors or chloride transporters [6,7,8]. It is yet to be determined how these drugs and the timing of their application (preclinical, during ischemia, or after revascularization) influence neuronal viability
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