Disruption of Ion Homeostasis in the Neurogliovascular Unit Underlies the Pathogenesis of Ischemic Cerebral Edema
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ORIGINAL ARTICLE
Disruption of Ion Homeostasis in the Neurogliovascular Unit Underlies the Pathogenesis of Ischemic Cerebral Edema Arjun Khanna & Kristopher T. Kahle & Brian P. Walcott & Volodymyr Gerzanich & J. Marc Simard
Received: 2 August 2013 / Revised: 22 October 2013 / Accepted: 6 November 2013 # Springer Science+Business Media New York 2013
Abstract Cerebral edema is a major cause of morbidity and mortality following ischemic stroke, but its underlying molecular pathophysiology is incompletely understood. Recent data have revealed the importance of ion flux via channels and transporters expressed in the neurogliovascular unit in the development of ischemia-triggered cytotoxic edema, vasogenic edema, and hemorrhagic conversion. Disruption of homeostatic mechanisms governing cell volume regulation and epithelial/endothelial ion transport due to ischemiaassociated energy failure results in the thermodynamically driven re-equilibration of solutes and water across the CSF– blood and blood–brain barriers that ultimately increases the brain’s extravascular volume. Additionally, hypoxia, inflammation, and other stress-triggered increases in the functional expression of ion channels and transporters normally expressed at low levels in the neurogliovascular unit cause disruptions in ion homeostasis that contribute to ischemic cerebral edema. Here, we review the pathophysiological significance of several molecular mediators of ion transport expressed in the neurogliovascular unit, including targets of A. Khanna : K. T. Kahle : B. P. Walcott Harvard Medical School, Boston, MA, USA A. Khanna : K. T. Kahle : B. P. Walcott (*) Department of Neurosurgery, Massachusetts General Hospital, 55 Fruit Street, White Building 502, Boston, MA 02114, USA e-mail: [email protected] V. Gerzanich Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA J. M. Simard (*) Departments of Neurosurgery, Pathology, and Physiology, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595, USA e-mail: [email protected]
existing FDA-approved drugs, which might be potential nodes for therapeutic intervention. Keywords Blood–brain barrier . Stroke . Ischemia . SUR1 . Glyburide . Bumetanide . Ion channel . Edema . NKCC1 . Tumor . Hemorrhage . TRPM4 . Hypertonic
Background Cerebral edema is a major cause of morbidity and mortality following ischemia in the brain. Ischemia causes an abrupt decline in the rate of oxidative metabolism in neurons, glia, and endothelial cells and, consequently, a rapid depletion of energy. The acute decline in cellular metabolism caused by hypoxia or anoxia inhibits energy-dependent mechanisms that are responsible for maintaining homeostatic solute gradients across neuroglial cell membranes, the vascular endothelium, and the choroid plexus endothelium. When these homeostatic mechanisms fail, edema results from a thermodynamically driven re-equilibration of solutes and water across cellular and endothelial barriers that ult
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