海马CA1区缺血后神经元持续死亡：缺血持续时间及细胞保护剂量的NBQX和SNX - 111对大鼠的影响

Continuing postischemic neuronal death in CA1: influence of ischemia duration and cytoprotective doses of NBQX and SNX-111 in rats.

作者信息

Colbourne F, Li H, Buchan A M, Clemens J A

机构信息

Department of Pathology, Alberta Stroke Program, Faculty of Medicine, University of Calgary, Alberta, Canada.

出版信息

Stroke. 1999 Mar;30(3):662-8. doi: 10.1161/01.str.30.3.662.

DOI:10.1161/01.str.30.3.662

PMID:10066868

Abstract

BACKGROUND AND PURPOSE

Transient forebrain ischemia results in a 24- to 72-hour delayed loss of CA1 neurons. Previous work has not assessed whether insult durations can vary the degree and maturation rate of CA1 injury and whether there are different ultrastructural features of death after brief or severe ischemia. We also tested whether known cytoprotective drugs achieve permanent or transient neuroprotection.

METHODS

In the first experiment, ischemia was induced for 5, 15, or 30 minutes with the use of the 4-vessel occlusion rat model with 1- to 28-day survival. Others subjected to 5 or 15 minutes of ischemia and allowed to survive for 14 or 7 days, respectively, were examined with electron microscopy. Finally, we determined whether NBQX (30 mg/kg x3 at 0 or 6 hours after ischemia), an AMPA antagonist, and SNX-111 (5 mg/kg at 6 hours after ischemia), an N-type Ca2+ channel antagonist, provided enduring CA1 protection against 10 minutes of ischemia.

RESULTS

CA1 damage was not detected at 24 hours. Thirty minutes of ischemia produced 47% and 84% CA1 damage at 2 and 3 days, respectively. A 15-minute occlusion yielded 11%, 74%, and 86% loss at 2, 3, and 7 days, respectively. Five minutes of ischemia produced an even slower progression with 24%, 52%, and 59% loss at 3, 7, and 14 days, respectively. Ultrastructural examination after 5 and 15 minutes of ischemia revealed necrosis with no morphological evidence of apoptosis. Both NBQX (P<0.021) and SNX-111 (P<0.001) significantly reduced CA1 death at 7 days (</=35%) but not at 28 days (>/=80%) compared with saline treatment ( approximately 79%).

CONCLUSIONS

Brief forebrain ischemia results in a slower progression of CA1 loss than more severe insults. Nonetheless, neuronal injury had necrotic, not apoptotic, morphology. NBQX and SNX-111 only postponed CA1 injury.

摘要

背景与目的

短暂性前脑缺血会导致CA1神经元在24至72小时后延迟死亡。以往的研究尚未评估缺血持续时间是否会影响CA1损伤的程度和成熟率，以及短暂或严重缺血后死亡的超微结构特征是否存在差异。我们还测试了已知的细胞保护药物是否能实现永久性或短暂性神经保护。

方法

在第一个实验中，使用四血管闭塞大鼠模型诱导缺血5、15或30分钟，存活1至28天。对分别经历5或15分钟缺血并存活14或7天的大鼠进行电子显微镜检查。最后，我们确定AMPA拮抗剂NBQX（缺血后0或6小时，30mg/kg×3）和N型钙通道拮抗剂SNX-111（缺血后6小时，5mg/kg）是否能为10分钟的缺血提供持久的CA1保护。

结果

24小时时未检测到CA1损伤。30分钟缺血在第2天和第3天分别导致47%和84%的CA1损伤。15分钟闭塞在第2、3和7天分别导致11%、74%和86%的神经元丢失。5分钟缺血导致的损伤进展更慢，在第3、7和14天分别有24%、52%和59%的神经元丢失。5分钟和15分钟缺血后的超微结构检查显示为坏死，无凋亡的形态学证据。与盐水处理（约79%）相比，NBQX（P<0.021）和SNX-111（P<0.001）在第7天均显著降低了CA1神经元死亡（≤35%），但在第28天没有（≥80%）。