Role of Chloride Transporters in Cerebral Ischemia

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Cerebral ischemia, produced by the lack of blood flow to the brain, is characterized by major disturbances in neuronal homeostasis in the hippocampus and other vulnerable brain regions. Oxygen-glucose deprivation (OGD), an in vitro model of cerebral ischemia, induces a rise in intracellular CI- in CA1 hippocampal neurons. Elevated intracellular CI- may lead to neuronal injury, as the disruption of the CI- gradient can limit GABA-mediated neuronal inhibition. Preliminary studies suggest that the NKCC-1 and KCC2 CI- cotransporters play an important role in OGD-induced CI- accumulation and subsequent neuronal damage; inhibiting CI- influx via the NKCC-1 cotransporter is neuroprotective, while inhibiting CI- efflux via the KCC2 cotransporter leads to more severe neuronal damage following OGD. To complement these studies, the role of CI- transporters in ischemic damage in vivo will be investigated following transient global cerebral ischemia in adult rats. In addition, the extent to which the NKCC-1 and KCC2 CI- cotransporters mediate the CI- accumulation following OGD will be determined using ratiometric CI- imaging in transgenic mice. Finally, the mechanism by which these transporters may be contributing to ischemic damage will be investigated by examining the expression and activity of NKCC-1 and KCC2 cotransporters following ischemia in vivo. An understanding of the mechanisms by which CI- transporters are involved in ischemic damage is essential to the progress of research in this field, and pharmacological manipulation of these cotransporters could provide a novel neuroprotective strategy for victims of stroke and cardiac arrest.