Acute ischemic injury of astrocytes is mediated by Na-K-Cl cotransport and not Ca2+ influx at a key point in white matter development

J Neuropathol Exp Neurol. 2004 Aug;63(8):856-71. doi: 10.1093/jnen/63.8.856.

Abstract

Cerebral palsy is a common birth disorder that frequently involves ischemic-type injury to developing white matter (WM). Dead glial cells are a common feature of this injury and here we describe a novel form of acute ischemic cell death in developing WM astrocytes. Ischemia, modeled by the withdrawal of oxygen and glucose, evoked [Ca2+]i increases and cell death in astrocytes in post-natal day 10 (P10) rat optic nerve (RON). Removing extracellular Ca2+ prevented increases in [Ca2+]i but increased the amount of cell death. Astrocytes showed rapid [Na+]i increases during ischemia and cell death was reduced to control levels by substitution of extracellular Na+ or Cl- or by perfusion with bumetanide, a selective Na-K-Cl cotransport (NKCC) blocker. Astrocytes showed marked swelling during ischemia in the absence of extracellular Ca2+, which was blocked by bumetanide. Raising the extracellular osmolarity to limit water uptake reduced ischemic astrocyte death to control levels. Ultrastructural examination showed that post-ischemic astrocytes had lost their processes and frequently were necrotic, effects partially prevented by bumetanide. At this point in development, therefore, NKCC activation in astrocytes during ischemia produces an osmo-regulatory challenge. Astrocytes can subsequently regulate their cell volume in a Ca2+-dependent fashion but this will require ATP hydrolysis and does not protect the cells against acute cell death.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / pathology*
  • Biological Transport, Active
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Calcium / metabolism*
  • Calcium / physiology
  • Calcium Signaling / physiology
  • Female
  • In Vitro Techniques
  • Male
  • Nerve Fibers, Myelinated / metabolism*
  • Nerve Fibers, Myelinated / pathology
  • Rats
  • Rats, Long-Evans
  • Sodium-Potassium-Chloride Symporters / metabolism*

Substances

  • Sodium-Potassium-Chloride Symporters
  • Calcium