Original Article

Translational Stroke Research

, Volume 5, Issue 1, pp 3-16

First online:

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

  • Arjun KhannaAffiliated withHarvard Medical SchoolDepartment of Neurosurgery, Massachusetts General Hospital
  • , Kristopher T. KahleAffiliated withHarvard Medical SchoolDepartment of Neurosurgery, Massachusetts General Hospital
  • , Brian P. WalcottAffiliated withHarvard Medical SchoolDepartment of Neurosurgery, Massachusetts General Hospital Email author 
  • , Volodymyr GerzanichAffiliated withDepartment of Neurosurgery, University of Maryland School of Medicine
  • , J. Marc SimardAffiliated withDepartments of Neurosurgery, Pathology, and Physiology, University of Maryland School of Medicine Email author 

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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.


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