Basic studies for prevention and treatment of the ischemic neuronal death

本研究的目的是探讨重复亚致死缺血是否能增强缺血耐受性。研究对象为72只成年雄性蒙古沙鼠。双侧颈动脉闭塞2min诱导亚致死性前脑缺血，或闭塞4min诱导致死性缺血。在致死性缺血前2、4周分别给药1次或8次（每2天或每4天）。致死性缺血性损伤7天后，灌注固定动物，估计海马CA1区神经元密度。采用28只动物进行免疫组织学研究。在单次或多次亚致死缺血后2w和4w（每2天）和致死缺血后2d对含有海马背侧的固定地鼠脑进行hsp70免疫染色。反复亚致死缺血沙鼠的CA1区神经元密度在最后一次亚致死缺血后4周显著高于单次亚致死缺血沙鼠（p< 0.05）。在单次或多次亚致死性缺血后2w和4w（每2天一次）和致死性缺血后2d均未观察到hsp70的诱导。本研究表明，重复亚致死缺血可增强缺血耐受性。另用5mm前脑缺血模型研究吲哚美辛对海马CA1区神经元死亡的影响。当脑温度（颞肌温度）保持在37.5 ~ 0.5时，吲哚美辛对神经元死亡没有改善作用。本研究表明，吲哚美辛对缺血性神经元损伤的保护作用是建立在降低脑温度的基础上的。

The aim of this study was to investigate whether repetitive sublethal ischemia enhances isehemic tolerance or not. Seventy-two adult male Mongolian gerbils were used. Bilateral carotid arteries were occluded for 2 min to induce sublethal forebrain ischemia, or 4 min to induce lethal ischemia. Sublethal ischemia were given once or eight times (every 2 days or 4 days) to the animals 2 or 4 weeks before lethal ischemia. Seven days after lethal ischemic insult, the animals were perfusion-fixed, and the neuronal densities in the hippocampal CA1 sector were estimated. Twenty-eight animals were used for the immunohistological study. At 2w and 4 w following single or multiple sublethal ischemia (every 2 days) and at 2d following the lethal ischemia immunostaining of fixed gebil brain containing the dorsal hippocampus against HSP7O was performed. In gerbils with repetitive sublethal ischemia, neuronal density of the CA1 sector was significantly (p<O.05) higher at 4 weeks following the last sublethal ischemia than that of the animals with single sublethal ischemia. Induction of HSP7O was seen neither at 2w and 4 w following single or multiple sublethal ischemia (every 2 days) nor at 2d following the lethal ischemia. The present study revealed that repetitive sublethal ischemia enhances ischemic tolerance.In another experiment using 5-mm forebrain iscemia model, effect of indomethacin to the neuronal death in the hippocampal CA1 sector was studied. Indomethacin did not ameliorate neuronal death under the condition that kept brain temperature (temporal muscle temperature) at 37.5 0.5. This study delineated that protective effect of indomethacin to the ischemic neyronal injury is based on the lowering effect of brain temperature.