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

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.

• Authors: Robert Thomas, Michael G Salter, Scott Wilke, Annalise Husen, Natalie Allcock, Mary Nivison, Aisha N Nnoli, Robert Fern
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 63 Issue 8 Pg. 856-71 (Aug 2004) ISSN: 0022-3069 [Print] England
• PMID: 15330340 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Sodium-Potassium-Chloride Symporters
• Calcium

Topics

• 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)