Failure and function of intracellular pH regulation in acute hypoxic-ischemic injury of astrocytes.
Astrocytes can die rapidly following ischemic and traumatic injury to the CNS. Brain acid-base status has featured prominently in theories of acute astrocyte injury. Failure of astrocyte pH regulation can lead to cell loss under conditions of severe acidosis. By contrast, the function of astrocyte pH regulatory mechanisms appears to be necessary for acute cell death following the simulation of transient ischemia and reperfusion. Severe lactic acidosis, and the failure of astrocytes to regulate intracellular pH (pH(i)) have been emphasized in brain ischemia under hyperglycemic conditions. Direct measurements of astrocyte pH(i) after cardiac arrest demonstrated a mean pH(i) of 5.3 in hyperglycemic rats. In addition, both in vivo and in vitro studies of astrocytes have shown similar pH levels to be cytotoxic. Whereas astrocytes exposed to hypoxia alone may require 12-24 h to die, acidosis has been found to exacerbate and speed hypoxic loss of these cells. Recently, astrocyte cultures were exposed to hypoxic, acidic media in which the large ionic perturbations characteristic of brain ischemia were simulated. Upon return to normal saline ("reperfusion"), the majority of cells died. This injury was dependent on external Ca2+ and was prevented by inhibition of reversed Na(+)-Ca2+ exchange, blockade of Na(+)-H+ exchange, or by low pH of the reperfusion saline. These data suggested that cytotoxic elevation of [Ca2+]i occurred during reperfusion due to a sequence of activated Na(+)-H+ exchange, cytosolic Na+ loading, and resultant reversal of Na(+)-Ca2+ exchange. The significance of this reperfusion model to ischemic astrocyte injury in vivo is discussed.
Chesler
Mitchell
M
Department of Neurosurgery and Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York.
D000138:Acidosis / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology*; D007424:Intracellular Fluid / Q000378:metabolism*