Kato H, Liu X H, Nakata N, Kogure K
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
Brain Res. 1993 Jul 2;615(2):240-4. doi: 10.1016/0006-8993(93)90033-j.
Recent experiments have shown that neuronal damage following repeated cerebral ischemic insults is more extensive than the damage after a single equivalent period of ischemia. To clarify the mechanism of this cumulative neuronal damage after repeated ischemia, we visualized the localization of heat shock protein-70 (HSP70), a marker of neuronal stress, with immunohistochemistry using a monoclonal antibody. Mongolian gerbils were subjected to three 2-min forebrain ischemic insults spaced at 1-h intervals and to a single 6-min period of ischemia. The animals were killed 24 and 48 h after ischemia. Hippocampal CA1 pyramidal neurons, which are destined to die, showed no HSP70 staining 24 and 48 h after three 2-min ischemic insults, but showed a mild to moderate staining after 6 min of ischemia, suggesting more severe damage after repeated ischemia. CA3 neurons, which are resistant to ischemia, were intensely stained with HSP70 antibody following 6 min of ischemia but was stained only slightly after three 2-min ischemic insults, showing less stress after repeated ischemia. Thus, thresholds for cell damage are obviously different among different cell populations within the hippocampus; the different neuronal populations respond differently to single and repetitive ischemia. The result suggests that cumulative neuronal damage after repeated sublethal ischemic insults is produced by increased susceptibility to subsequent insults when ischemic stress reaches certain thresholds that are different among different neuronal populations.
最近的实验表明，反复脑缺血损伤后神经元损伤比单次同等时长的缺血损伤更广泛。为了阐明反复缺血后这种累积性神经元损伤的机制，我们使用单克隆抗体通过免疫组织化学方法观察了神经元应激标志物热休克蛋白70（HSP70）的定位。将蒙古沙鼠进行三次2分钟的前脑缺血损伤，每次间隔1小时，以及一次6分钟的缺血损伤。在缺血后24小时和48小时处死动物。注定死亡的海马CA1锥体神经元在三次2分钟缺血损伤后24小时和48小时未显示HSP70染色，但在缺血6分钟后显示轻度至中度染色，表明反复缺血后损伤更严重。对缺血有抗性的CA3神经元在缺血6分钟后被HSP70抗体强烈染色，但在三次2分钟缺血损伤后仅轻微染色，表明反复缺血后应激较小。因此，海马内不同细胞群体的细胞损伤阈值明显不同；不同的神经元群体对单次和重复性缺血的反应不同。结果表明，反复亚致死性缺血损伤后的累积性神经元损伤是由于当缺血应激达到不同神经元群体中不同的特定阈值时，对后续损伤的易感性增加所致。
