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

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.
AuthorsRobert Thomas, Michael G Salter, Scott Wilke, Annalise Husen, Natalie Allcock, Mary Nivison, Aisha N Nnoli, Robert Fern
JournalJournal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 63 Issue 8 Pg. 856-71 (Aug 2004) ISSN: 0022-3069 [Print] United States
PMID15330340 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Sodium-Potassium-Chloride Symporters
  • Calcium
  • Acute Disease
  • Animals
  • Astrocytes (metabolism, pathology)
  • Biological Transport, Active
  • Brain Ischemia (metabolism, pathology)
  • Calcium (metabolism, physiology)
  • Calcium Signaling (physiology)
  • Female
  • In Vitro Techniques
  • Male
  • Nerve Fibers, Myelinated (metabolism, pathology)
  • Rats
  • Rats, Long-Evans
  • Sodium-Potassium-Chloride Symporters (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: