Aronica E M, Gorter J A, Grooms S, Kessler J A, Bennett M V, Zukin R S, Rosenbaum D M
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7115-20. doi: 10.1073/pnas.95.12.7115.
Aurintricarboxylic acid (ATA), an inhibitor of endonuclease activity and other protein-nucleic acid interactions, blocks apoptosis in several cell types and prevents delayed death of hippocampal pyramidal CA1 neurons induced by transient global ischemia. Global ischemia in rats and gerbils induces down-regulation of GluR2 mRNA and increased alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced Ca2+ influx in CA1 before neurodegeneration. This result and neuroprotection by antagonists of AMPA receptors suggests that formation of AMPA receptors lacking GluR2, and therefore Ca2+ permeable, leads to excessive Ca2+ influx in response to endogenous glutamate; the resulting delayed neuronal death in CA1 exhibits many characteristics of apoptosis. In this study, we examined the effects of ATA on expression of mRNAs encoding glutamate receptor subunits in gerbil hippocampus after global ischemia. Administration of ATA by injection into the right cerebral ventricle 1 h before (but not 6 h after) bilateral carotid occlusion prevented the ischemia-induced decrease in GluR2 mRNA expression and the delayed neurodegeneration. These findings suggest that ATA is neuroprotective in ischemia by blocking the transcriptional changes leading to down-regulation of GluR2, rather than by simply blocking endonucleases, which presumably act later after Ca2+ influx initiates apoptosis. Maintaining formation of Ca2+ impermeable, GluR2 containing AMPA receptors could prevent delayed death of CA1 neurons after transient global ischemia, and block of GluR2 down-regulation may provide a further strategy for neuroprotection.
金精三羧酸（ATA）是一种核酸内切酶活性及其他蛋白质 - 核酸相互作用的抑制剂，可阻断多种细胞类型的凋亡，并防止短暂性全脑缺血诱导的海马锥体细胞CA1神经元延迟死亡。大鼠和沙鼠的全脑缺血会导致GluR2 mRNA下调，并在神经变性之前增加CA1区α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）诱导的Ca2+内流。这一结果以及AMPA受体拮抗剂的神经保护作用表明，缺乏GluR2因而具有Ca2+通透性的AMPA受体的形成，会导致对内源性谷氨酸的过度Ca2+内流；由此导致的CA1区延迟性神经元死亡表现出许多凋亡特征。在本研究中，我们检测了ATA对全脑缺血后沙鼠海马中编码谷氨酸受体亚基的mRNA表达的影响。在双侧颈动脉闭塞前1小时（而非6小时后）经右脑室注射ATA，可防止缺血诱导的GluR2 mRNA表达降低和延迟性神经变性。这些发现表明，ATA在缺血中具有神经保护作用，其机制是阻断导致GluR2下调的转录变化，而不是简单地阻断核酸内切酶，核酸内切酶可能在Ca2+内流引发凋亡后更晚发挥作用。维持含有GluR2的Ca2+不通透性AMPA受体的形成，可防止短暂性全脑缺血后CA1神经元的延迟死亡，而阻断GluR2下调可能为神经保护提供进一步的策略。
