Dietrich W D, Lin B, Globus M Y, Green E J, Ginsberg M D, Busto R
Department of Neurology, University of Miami, School of Medicine, Florida 33101, USA.
J Cereb Blood Flow Metab. 1995 Nov;15(6):960-8. doi: 10.1038/jcbfm.1995.122.
In contrast to intraischemic hypothermia, immediate postischemic hypothermia (30 degrees C) has been shown to delay but not chronically protect the CA1 hippocampus from transient global forebrain ischemia. The inability of a relatively short postischemic hypothermic period to protect chronically might involve a delayed or secondary injury mechanism. We determined whether delayed treatment with the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine), alone or in combination with immediate postischemic hypothermia, would chronically protect histopathologically. Wistar rats underwent 10 min of normothermic forebrain ischemia induced by bilateral common carotid artery occlusion plus hypotension (50 mg Hg). Four ischemia groups were studied after normothermic (37 degrees C) ischemia: no treatment; 3 h of immediate postischemic hypothermia (30 degrees C); delayed MK-801 treatment (4 mg/kg) on postischemic days 3, 5, and 7; and postischemic hypothermia combined with multiple MK-801 treatments. Two months after the ischemic insult, rats were perfusion-fixed for quantitative histopathological assessment. Postischemic hypothermia alone or MK-801 treatment alone failed to protect the CA1 hippocampus chronically. However, immediate postischemic hypothermia combined with delayed MK-801 treatment led to significant increases in normal CA1 neuron counts per microscopic field compared with normothermic ischemia. For example, neuronal counts within the hippocampal CA1 areas were 58 +/- 39 (mean +/- SD) in normothermic ischemic rats compared with 395 +/- 198 in rats treated with postischemic hypothermia and MK-801. Chronic survival also led to pronounced striatal damage. Within the dorsolateral striatum, significant protection was documented with either postischemic hypothermia alone or delayed MK-801 treatment alone.
与缺血期间低温不同，缺血后即刻低温（30摄氏度）已被证明可延迟但不能长期保护海马CA1区免受短暂性全脑缺血的损伤。相对较短的缺血后低温期无法长期保护可能涉及延迟或继发性损伤机制。我们确定了非竞争性N-甲基-D-天冬氨酸受体拮抗剂MK-801（地佐环平）单独或与缺血后即刻低温联合进行延迟治疗是否能在组织病理学上提供长期保护。Wistar大鼠通过双侧颈总动脉闭塞加低血压（50 mmHg）诱导进行10分钟的常温全脑缺血。在常温（37摄氏度）缺血后研究了四个缺血组：不治疗；缺血后即刻低温（30摄氏度）3小时；在缺血后第3、5和7天进行延迟MK-801治疗（4 mg/kg）；缺血后低温与多次MK-801治疗联合。缺血损伤两个月后，对大鼠进行灌注固定以进行定量组织病理学评估。单独的缺血后低温或单独的MK-801治疗均未能长期保护海马CA1区。然而，与常温缺血相比，缺血后即刻低温联合延迟MK-801治疗导致每个显微镜视野中正常CA1神经元数量显著增加。例如，常温缺血大鼠海马CA1区的神经元数量为58±39（平均值±标准差），而缺血后低温和MK-801治疗的大鼠为395±198。长期存活还导致纹状体明显损伤。在背外侧纹状体内，单独的缺血后低温或单独的延迟MK-801治疗均显示有显著的保护作用。
