ANOXIA-INDUCED NEURONAL INJURY - ROLE OF NA-DEPENDENT TRANSPORT( ENTRY AND NA+)

An important cause of anoxia-induced nerve injury involves the disrupt ion of the ionic balance that exists across the neuronal membrane. Thi s loss of ionic homeostasis results in an increase in intracellular ca lcium, sodium, and hydrogen and is correlated with cell injury and dea th. Using time-lapse confocal microscopy, we have previously reported that nerve cell injury is mediated largely by sodium and that removing extracellular sodium prevents the anoxia-induced morphological change s. In this study, we hypothesized that sodium enters neurons via speci fic mechanisms and that the pharmacologic blockade of sodium entry wou ld prevent nerve damage. In cultured neocortical neurons we demonstrat e that replacing extracellular sodium with NMDG(+) prevents anoxia-ind uced morphological changes. With sodium in the extracellular fluid, va rious routes of sodium entry were examined, including voltage-sensitiv e sodium channels, glutamate receptor channels, and sodium-dependent c hloride-bicarbonate exchange. Blockade of these routes had no effect. Amiloride, however, prevented the morphological changes induced by ano xia lasting 10, 15, or 20 min. At doses of 10 mu M-1 mM, amiloride pro tected neurons in a dose-dependent fashion. We argue that amiloride ac ts on a Na+-dependent exchanger (e.g., Na+-Ca2+) and present a model t o explain these findings in the context of the neuronal response to an oxia. (C) 1997 Academic Press.