[Response of Na+/Ca2+ antiporter to ischemia and glial/neuronal death]

Brain ischemia produces morphologic and biochemical alterations in astrocytes. This mini-review summarizes astrocytic responses to brain ischemia including our studies on the neuronal and astrocytic Na(+)-Ca2+ exchanger (NCX). NCX is considered to cause Ca2+ efflux (forward mode) or Ca2+ influx (reverse mode), depending on the electrochemical gradient of Na+ across the plasma membranes and membrane potential. We demonstrated that NCX is present in cultured neurons and astrocytes and that there are differences in their properties and distribution ratio of the isoforms between neurons and astrocytes. We also found that Ca2+ depletion followed by reperfusion with Ca(2+)-containing medium caused cell death in cultured astrocytes (Ca2+ paradox-like injury), but not in neurons. The study, carried out by the use of a specific antisense oligomer, provides direct evidence that Ca2+ paradox-like injury is mediated by NCX in the reverse mode. The injury was attenuated by inhibitors of the Na(+)-Ca2+ exchanger, heat shock protein and the calcineurin inhibitor FK506. In a preliminary experiment, we found that brain ischemia decreases the mRNA level of NCX in the hippocampus. Further studies on activation and cell injury of astrocytes will contribute to development of new drugs that modulate the function of astrocytes.