THE ROLE OF EARLY CA2+ INFLUX IN THE PATHOGENESIS OF DELAYED NEURONALDEATH AFTER BRIEF FOREBRAIN ISCHEMIA IN GERBILS

To examine the role of calcium influx in the early phase after brief f orebrain ischemia and subsequent delayed neuronal cell death in the hi ppocampus, Ca-45 autoradiography and electron microscopic cytochemistr y, by a combined oxalate-pyroantimonate method, were carried out in ge rbil brains after 5 min bilateral common carotid arterial occlusion. F urther, neuronal damage during the ischemic and postischemic periods w as determined by conventional or immunohistochemical staining for micr otubule-associated protein 2 (MAP2) with and without calcium-entry blo ckers. Ca-45 autoradiography showed a high peak of calcium in the hipp ocampus at 5 min of recirculation. Electron cytochemical microscopy al so demonstrated accumulation of intracellular calcium pyroantimonate d eposits in the neuronal cells in all regions. At 30 min of reperfusion , amounts of calcium in the hippocampus returned to the control levels , and intracellular dense calcium pyroantimonate deposits were reduced in these areas. Loss of the reaction for MAP2 was noted in the medial CA1 of the hippocampus immediately after 5 min ischemia and at 5 and 30 min after reperfusion. MK-801 (10 mg kg-1), an N-methyl-D-aspartate (NMDA) receptor antagonist, injected intraperitoneally 1 h before isc hemia, suppressed the early increase of calcium in the forebrain and n euronal cell necrosis in the CA1. However, neither injection of MK-801 30 min after reperfusion nor preischemic treatment with 0.5 mg kg-1 N imodipine or 1 mg kg-1 Nicardipine, voltage-sensitive calcium channel antagonists, prevented neuronal death. In immunohistochemical staining for MAP2, the ischemic lesion in the medial CA1 maintained after 5 mi n ischemia and the subsequent early reperfusion period in the untreate d brains was protected by the preischemic injection of 10 mg kg-1 MK-8 01, but was not restored by the injection of 0.5 mg kg-1 Nimodipine or 1 mg kg - 1 Nicardipine. In conclusion, it is suggested that an early excess of calcium influx could be caused mainly by excitatory amino a cid overload through NMDA receptor-mediated calcium channels during th e ischemic and early postischemic periods.