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Disruption of Ion Homeostasis in the Neurogliovascular Unit Underlies the Pathogenesis of Ischemic Cerebral Edema

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 ischemia-associated 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 existing FDA-approved drugs, which might be potential nodes for therapeutic intervention.

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Acknowledgment

This work was supported by grants to JMS from the National Heart, Lung and Blood Institute (HL082517) and the National Institute of Neurological Disorders and Stroke (NS061808) and to BPW from the Brain Aneurysm Foundation.

Compliance with Ethics Requirements

JMS holds a US patent (#7, 285, 574), “A novel non-selective cation channel in neural cells and methods for treating brain swelling,” and is a member of the Scientific Advisory Board and holds shares in Remedy Pharmaceuticals. No support was provided by Remedy Pharmaceuticals to JMS for this project.

This article does not contain any studies with human or animal subjects.

Conflict of Interest

Arjun Khanna, Kristopher T. Kahle, Brian P. Walcott, Volodymyr Gerzanich, and J Marc Simard declare that they have no conflict of interest.

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Khanna, A., Kahle, K.T., Walcott, B.P. et al. Disruption of Ion Homeostasis in the Neurogliovascular Unit Underlies the Pathogenesis of Ischemic Cerebral Edema. Transl. Stroke Res. 5, 3–16 (2014). https://doi.org/10.1007/s12975-013-0307-9

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Keywords

  • Blood–brain barrier
  • Stroke
  • Ischemia
  • SUR1
  • Glyburide
  • Bumetanide
  • Ion channel
  • Edema
  • NKCC1
  • Tumor
  • Hemorrhage
  • TRPM4
  • Hypertonic