Rod M R, Auer R N
Department of Pathology, University of Calgary, Alberta, Canada.
Stroke. 1992 May;23(5):725-32. doi: 10.1161/01.str.23.5.725.
We explored the effectiveness of dual blockade of calcium channels in preventing ischemic necrosis in a rat model of transient forebrain ischemia.
To assess all the major brain regions, the entire brain was subserially sectioned and examined histologically 1 week after ischemia in 44 male Wistar rats. Brain temperature was monitored and controlled to avoid hypothermia or intergroup temperature differences at the time drugs were administered. All regimens were begun 20 minutes after ischemia. Treated animals received either the L-type calcium channel blocker nimodipine (0.25 microgram/min x 24-hour i.v. infusion), the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine; 5 mg/kg i.v.), or both regimens in combination.
In the neocortex (p less than 0.05) and striatum (p less than 0.05), only double-treated animals showed a statistically significant reduction in neuronal necrosis. Dual therapy eliminated neuronal necrosis in the caudate nucleus entirely. In the septal (densely ischemic) hippocampus, protection was weak and inconsistent (0.012 less than p less than 0.788), but in the temporal (incompletely ischemic) hippocampus, the dual-treated group showed the most significant reduction (p less than 0.006).
We conclude that the combination of nimodipine and MK-801, if begun 20 minutes after ischemia, may offer a neuroprotective effect against neuronal necrosis in transient forebrain ischemia and that protection is maximal in the major extrahippocampal brain regions.
我们在大鼠短暂性前脑缺血模型中探究了钙通道双重阻断在预防缺血性坏死方面的有效性。
为评估所有主要脑区，对44只雄性Wistar大鼠在缺血1周后进行全脑连续切片并进行组织学检查。监测并控制脑温，以避免低温或给药时组间温度差异。所有方案均在缺血20分钟后开始。治疗组动物分别接受L型钙通道阻滞剂尼莫地平（0.25微克/分钟×24小时静脉输注）、非竞争性N-甲基-D-天冬氨酸受体拮抗剂MK-801（地佐环平；5毫克/千克静脉注射），或两种方案联合使用。
在新皮质（p<0.05）和纹状体（p<0.05）中，只有联合治疗组动物的神经元坏死有统计学意义的显著减少。双重治疗完全消除了尾状核中的神经元坏死。在隔区（严重缺血）海马中，保护作用微弱且不一致（0.012<p<0.788），但在颞叶（不完全缺血）海马中，联合治疗组的减少最为显著（p<0.006）。
我们得出结论，尼莫地平与MK-801联合使用，如果在缺血20分钟后开始，可能对短暂性前脑缺血中的神经元坏死具有神经保护作用，且在主要的海马外脑区保护作用最大。
