Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death
Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death
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DOI：
10.1523/jneurosci.1713-04.2004
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发表时间：
2004-11-03
影响因子：
5.3
通讯作者：
Zukin, RS
中科院分区：
文献类型：
--
作者：
Calderone, A;Jover, T;Zukin, RS
短暂性全脑缺血诱导细胞内Zn 2+的延迟上升，这可能是通过谷氨酸受体2（GluR 2）缺乏AMPA受体（AMPAR）介导的，以及海马CA 1神经元的选择性延迟死亡。锌离子在体内毒性的分子机制还没有得到很好的描述。在这里，我们展示了惊人的发现，在缺血前30分钟（早期CaEDTA）或在缺血后48 - 60小时（晚期CaEDTA），但不是3 - 6小时，脑室内注射高亲和力Zn 2+螯合剂钙EDTA（CaEDTA），提供了类似于50%（晚期CaEDTA）至75%（早期CaEDTA）动物的CA 1神经元的强大保护。我们还表明，锌+行为通过时间不同的机制，以促进神经元死亡。早期CaEDTA减弱缺血诱导的GluR 2 mRNA和蛋白下调（并通过推断形成Zn 2+渗透性AMPAR），延迟Zn 2+升高和神经元死亡。这些结果表明，Zn ~（2+）作用于GluR 2基因下调的上游步骤，并涉及Zn ~（2+）的转录调控和/或GluR 2 mRNA的稳定性。早期CaEDTA还阻断了线粒体释放细胞色素c和Smac/DIABLO（低pI的第二种caspase衍生激活剂/凋亡蛋白结合蛋白的直接抑制剂）、caspase-3活性（但不阻断caspase-3切割）、p75（NTR）诱导和DNA片段化。这些发现表明，CaEDTA保持线粒体外膜的功能完整性，并阻止caspase死亡级联反应。在GluR 2下调和半胱天冬酶激活的时候晚期注射CaEDTA抑制了Zn 2+、p75（NTR）诱导、DNA片段化和细胞死亡的延迟上升。晚期给予CaEDTA的神经保护作用的发现对于与全脑缺血相关的迟发性神经元死亡的干预具有显著的意义。
Transient global ischemia induces a delayed rise in intracellular Zn2+, which may be mediated via glutamate receptor 2 (GluR2)-lacking AMPA receptors (AMPARs), and selective, delayed death of hippocampal CA1 neurons. The molecular mechanisms underlying Zn2+ toxicity in vivo are not well delineated. Here we show the striking finding that intraventricular injection of the high-affinity Zn2+ chelator calcium EDTA (CaEDTA) at 30 min before ischemia ( early CaEDTA) or at 48 - 60 hr ( late CaEDTA), but not 3 - 6 hr, after ischemia, afforded robust protection of CA1 neurons in similar to 50% ( late CaEDTA) to 75% ( early CaEDTA) of animals. We also show that Zn2+ acts via temporally distinct mechanisms to promote neuronal death. Early CaEDTA attenuated ischemia-induced GluR2 mRNA and protein downregulation ( and, by inference, formation of Zn2+-permeable AMPARs), the delayed rise in Zn2+, and neuronal death. These findings suggest that Zn2+ acts at step(s) upstream from GluR2 gene downregulation and implicate Zn2+ in transcriptional regulation and/or GluR2 mRNA stability. Early CaEDTA also blocked mitochondrial release of cytochrome c and Smac/DIABLO ( second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with low pI), caspase-3 activity ( but not procaspase-3 cleavage), p75(NTR) induction, and DNA fragmentation. These findings indicate that CaEDTA preserves the functional integrity of the mitochondrial outer membrane and arrests the caspase death cascade. Late injection of CaEDTA at a time when GluR2 is downregulated and caspase is activated inhibited the delayed rise in Zn2+, p75(NTR) induction, DNA fragmentation, and cell death. The finding of neuroprotection by late CaEDTA administration has striking implications for intervention in the delayed neuronal death associated with global ischemia.