Exacerbated brain edema in a rat streptozotocin model of hyperglycemic ischemic stroke: Evidence for involvement of blood-brain barrier Na-K-Cl cotransport and Na/H exchange

J Cereb Blood Flow Metab. 2019 Sep;39(9):1678-1692. doi: 10.1177/0271678X18770844. Epub 2018 May 9.

Abstract

Cerebral edema is exacerbated in diabetic ischemic stroke through poorly understood mechanisms. We showed previously that blood-brain barrier (BBB) Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) are major contributors to edema formation in normoglycemic ischemic stroke. Here, we investigated whether hyperglycemia-exacerbated edema involves changes in BBB NKCC and NHE expression and/or activity and whether inhibition of NKCC or NHE effectively reduces edema and injury in a type I diabetic model of hyperglycemic stroke. Cerebral microvascular endothelial cell (CMEC) NKCC and NHE abundances and activities were determined by Western blot, radioisotopic flux and microspectrofluorometric methods. Cerebral edema and Na in rats subjected to middle cerebral artery occlusion (MCAO) were assessed by nuclear magnetic resonance methods. Hyperglycemia exposures of 1-7d significantly increased CMEC NKCC and NHE abundance and activity. Subsequent exposure to ischemic factors caused more robust increases in NKCC and NHE activities than in normoglycemic CMEC. MCAO-induced edema and brain Na uptake were greater in hyperglycemic rats. Intravenous bumetanide and HOE-642 significantly attenuated edema, brain Na uptake and ischemic injury. Our findings provide evidence that BBB NKCC and NHE contribute to increased edema in hyperglycemic stroke, suggesting that these Na transporters are promising therapeutic targets for reducing damage in diabetic stroke.

Keywords: Blood–brain barrier; brain edema; cerebral ischemia; hyperglycemia; sodium transporters.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Brain Edema / complications*
  • Brain Edema / metabolism
  • Brain Edema / pathology
  • Cattle
  • Cell Line
  • Hyperglycemia / chemically induced
  • Hyperglycemia / complications*
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Infarction, Middle Cerebral Artery / complications*
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Hydrogen Exchangers / analysis
  • Sodium-Hydrogen Exchangers / metabolism*
  • Sodium-Potassium-Chloride Symporters / analysis
  • Sodium-Potassium-Chloride Symporters / metabolism*
  • Streptozocin

Substances

  • Sodium-Hydrogen Exchangers
  • Sodium-Potassium-Chloride Symporters
  • Streptozocin