ALPHA(2)-ADRENERGIC AGONISTS REDUCE GLUTAMATE RELEASE AND GLUTAMATE RECEPTOR-MEDIATED CALCIUM CHANGES IN HIPPOCAMPAL SLICES DURING HYPOXIA

The mechanisms by which alpha(2)-adrenergic agonists reduce ischemic b rain damage are not clear. In ischemia-vulnerable hippocampal neurons we tested whether alpha(2)-agonists reduce glutamate efflux and glutam ate receptor-mediated increase of cytosolic free calcium. Brain slices (300 mu m thick) from rat hippocampus were loaded with fura-2 for mea surements of cytosolic free calcium with a microscope fluorometer. Cha nge of cytosolic calcium in CA1 neurons during application of N-methyl -D-aspartate (NMDA) was measured, as were calcium changes during simul ated ischemia (hypoxia, NaCN, iodoacetate) or hypoxia plus high glutam ate concentration (pO(2) = 25 mmHg, 3 mM glutamate). In other slices, glutamate efflux evoked by anoxia (pO(2) = 25 mmHg, 100 mu M NaCN) was measured.The selective alpha(2)-agonist mivazerol (1 mu M) decreased NMDA receptor-mediated calcium changes in hippocampal CA1 neurons by 2 8% (p = 0.0079). With hypoxia and 3 mM glutamate, 1 mu M mivazerol red uced early peak calcium changes in CA1 neurons by 57% (p = 0.0007). An alpha(2)-antagonist (rauwolscine, 1 mu M) blocked this. Mivazerol did not reduce the rate of calcium change during simulated ischemia. Clon idine (0.1 mu M), a partial alpha(2)-agonist, decreased glutamate/hypo xia-mediated calcium changes in CA1 (p = 0.01), but 1 mu M clonidine, which stimulates alpha(1)-receptors, did not. Mivazerol decreased hypo xia and KCl-evoked glutamate release by 50% and 75% (p < 0.01), respec tively. In addition, 1 mu M mivazerol reduced lactate dehydrogenase le akage rate from brain slices during anoxia by 61% (p = 0.018). Thus, a lpha(2)-receptors influence glutamate release, calcium changes, and ce ll damage in ischemia-vulnerable hippocampal neurons. These effects ma y contribute to the cerebroprotective actions of alpha(2)-agonists. Co pyright (C) 1996 Elsevier Science Ltd.