Mechanism of ischemic neuronal death

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We summarize herewith new findings obtained during the threeyear-research project "Mechanism of ischemic neuronal death".1. Delayed neuronal death, selectively occurred in hippocampal CAl area 2-3 days after transient forebrain ischemia, is highly sensitive to cerebral temperature during the insult, and mild hypothermia such as lowering by 4 C almost completely protected neurons from damage. Spontaneous firing of CAl neurons, which totally disappeared during the insult, began to recover along with reperfusion of brain, but the firing frequency decidedly did not exceed the preischemic level ; a fact which is not in accordance with, previous notion that delayed neuronal death is due to postischemic hyperexcitability of CAl neurons.2. Microdialysis studies in gerbil hippocampus coupled with an enzymatic cycling method revealed that forebrain ischemia induced a prompt and hypothermia-sensitive release of glutamate in a large scale (15-20 times preischemic level at 5 min ischemia) followed by a quick return to preischemic range.3. Using gerbil hippocampal slices, we developed a microfluorometry on a fluorescence microscope - a supersensitive video camera - an image analyzer setup. Introducing hypoxiahypoglycemia of perfusion medium induced regionally non-selective glutamate release from whole hippocampal area, within 20 sec of the insult, which followed by regionally selective calcium accumulation in CAl area accompanied by membrane depolarization within 200 sec. Mild hypothermia prolonged the latency in a dose-dependent manner. Taking -together, ischemia induced glutamate release followed by intracellular calcium accumulation is likely to be most crucial in early stage of ischemic neuronal damage.