Urban L, Neill K H, Crain B J, Nadler J V, Somjen G G
Department of Cell Biology, Duke University Medical Center, Durham, N.C. 27710.
Stroke. 1990 Nov;21(11 Suppl):III23-7.
Transient forebrain ischemia leads to the delayed degeneration of CA1b hippocampal pyramidal cells. In previous studies using the gerbil carotid occlusion model, we demonstrated that CA1b pyramidal cell degeneration is preceded by a period of enhanced excitatory transmission. Experiments with hippocampal slices prepared after 5 minutes of bilateral carotid artery occlusion show that ischemia enhances excitatory synaptic transmission and reduces pyramidal cell excitability before it abolishes synaptic function. In the present study, we tested the hypothesis that these effects require the activation of N-methyl-D-aspartate receptors during the postischemic period. Hippocampal slices were prepared 20-30 minutes after carotid occlusion, and Schaffer collateral-commissural input-output curves were constructed from recordings made every 30-60 minutes for 11-14 hours. Inclusion of the selective, reversible N-methyl-D-aspartate receptor antagonist 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid in the superfusion medium completely prevented the progressive loss of pyramidal cell excitability that normally follows this ischemic insult. This antagonist also prevented the postischemic increases in the duration and initial slope of the focally-recorded excitatory postsynaptic potential. The antagonist could still partially block the effects of transient forebrain ischemia when treatment was delayed for 4 hours. Our results confirm that the deleterious electrophysiologic changes in area CA1b depend on the continuing activation of N-methyl-D-aspartate receptors. Delayed ischemic neuronal death may result, in part, from excessive synaptic excitation during the postischemic period. However, other factors that are eliminated by preparing hippocampal slices appear to play an important role as well.
短暂性前脑缺血会导致海马CA1b区锥体细胞的延迟性退变。在之前使用沙鼠颈动脉闭塞模型的研究中，我们证明CA1b区锥体细胞退变之前会有一段兴奋性传递增强的时期。对双侧颈动脉闭塞5分钟后制备的海马脑片进行的实验表明，缺血在消除突触功能之前会增强兴奋性突触传递并降低锥体细胞的兴奋性。在本研究中，我们检验了这样一个假设，即这些效应需要在缺血后时期激活N-甲基-D-天冬氨酸受体。在颈动脉闭塞后20 - 30分钟制备海马脑片，并在11 - 14小时内每隔30 - 60分钟进行记录，构建Schaffer侧支-连合输入-输出曲线。在灌流液中加入选择性、可逆的N-甲基-D-天冬氨酸受体拮抗剂3-((±)-2-羧基哌嗪-4-基)-丙基-1-膦酸，完全阻止了通常在这种缺血性损伤后发生的锥体细胞兴奋性的逐渐丧失。这种拮抗剂还阻止了缺血后局部记录的兴奋性突触后电位的持续时间和起始斜率的增加。当治疗延迟4小时时，该拮抗剂仍能部分阻断短暂性前脑缺血的效应。我们的结果证实，CA1b区有害的电生理变化取决于N-甲基-D-天冬氨酸受体的持续激活。延迟性缺血性神经元死亡可能部分源于缺血后时期过度的突触兴奋。然而，通过制备海马脑片而被消除的其他因素似乎也起着重要作用。
