Differential Roles of NMDA Receptor Subtypes in Ischemic Neuronal Cell Death and Ischemic Tolerance
Differential Roles of NMDA Receptor Subtypes in Ischemic Neuronal Cell Death and Ischemic Tolerance
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DOI：
10.1161/strokeaha.108.521898
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发表时间：
2008-11-01
期刊：
影响因子：
8.3
通讯作者：
Xiong, Zhi-Qi
中科院分区：
文献类型：
--
作者：
Chen, Min;Lu, Ting-Jia;Xiong, Zhi-Qi
背景和目的：在动物模型中，谷氨酸受体NMDA亚型的激活与缺血诱导的细胞损伤以及缺血预适应后缺血耐受的建立有关。在大鼠短暂性全脑缺血模型中，我们研究了NR2A型和NR2B型NMDA受体在缺血细胞死亡和耐受中的作用。用荧光素B和尼氏染色分析神经元损伤情况。用Western blotting和免疫组织化学方法检测CREB的磷酸化。结果：NR2A亚型特异性拮抗剂NVP-AAM077可促进短暂性全脑缺血后神经元死亡，阻断缺血耐受的诱导。相反，NR2B亚型特异性拮抗剂ifenprodil可减轻缺血细胞死亡并增强预适应诱导的神经保护。此外，选择性地阻断含有NMDA受体的NR2A-，而不是NR2B-，可以抑制缺血诱导的CREB的磷酸化以及随后CREB靶基因cpg15和bdnf的上调。结论-我们发现含有NR2A-和NR2B-的NMDA受体亚型在缺血性神经元死亡和缺血耐受中发挥着不同的作用，为卒中患者药物的开发提供了有吸引力的新策略。(笔划。2008；39：3042-3048。)
Background and Purpose-Activation of NMDA subtypes of glutamate receptors is implicated in cell damage induced by ischemia as well as for the establishment of ischemic tolerance after ischemic preconditioning in animal models. We investigated the contributions of NR2A- and NR2B-containing NMDA receptors to ischemic cell death and ischemic tolerance in a rat model of transient global ischemia.Methods-Transient global ischemia was produced in rats by 4-vessel occlusion. Neuronal injury was analyzed by Fluoro-Jade B and Nissl staining. Phosphorylation of CREB was detected by Western blotting and immunohistochemistry. In situ hybridization and reverse transcriptase-polymerase chain reaction were used to evaluate the mRNA level of cpg15 and bdnf.Results-NR2A subtype-specific antagonist NVP-AAM077 enhanced neuronal death after transient global ischemia and abolished the induction of ischemic tolerance. In contrast, NR2B subtype-specific antagonist ifenprodil attenuated ischemic cell death and enhanced preconditioning-induced neuroprotection. Furthermore, selectively blocking NR2A-, but not NR2B-, containing NMDA receptors inhibited ischemia-induced phosphorylation of CREB and the subsequent upregulation of CREB target genes such as cpg15 and bdnf.Conclusions-We found that NR2A- and NR2B- containing NMDA receptor subtypes play differential roles in ischemic neuronal death and ischemic tolerance, suggesting attractive new strategies for the development of drugs for patients with stroke. (Stroke. 2008; 39: 3042-3048.)