Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death
Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death
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DOI：
10.1073/pnas.0505408102
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发表时间：
2005-08-23
影响因子：
11.1
通讯作者：
Bennett, MVL
中科院分区：
文献类型：
--
作者：
Noh, KM;Yokota, H;Bennett, MVL
在动物实验中诱导的短暂性全脑或前脑缺血可导致海马CA 1区锥体神经元的选择性、延迟性神经元死亡。一个显着的特点是延迟上升细胞内游离Zn 2+在CA 1神经元的发病前，组织学检测到的细胞死亡。在这里，我们表明，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体（AMPAR）在Schaffer侧支CA 1突触缺血后海马表现出Ca 2 +/Zn 2+渗透，Glu受体2（GluR 2）缺乏AMPAR的Zn 2+和细胞死亡之前的上升。在缺血后42小时，AMPA兴奋性突触后电流表现出明显的内向整流和显着的敏感性1-萘基乙酰精胺（Naspm），GluR 2缺乏AMPAR的选择性通道阻滞剂。在对照组海马，AMPA兴奋性突触后电流呈线性，对Naspm相对不敏感。在损伤后9-40 h，脑内注射Naspm，可显著降低缺血后CA 1神经元细胞内游离Zn 2+的晚期升高，并对缺血诱导的细胞死亡提供部分保护。这些结果表明，GluR 2缺乏AMPA受体在缺血诱导的游离Zn 2+和CA 1神经元死亡的上升，虽然在Zn 2+的上升时的直接作用是未经证实的。这种受体亚型似乎是一个重要的治疗目标，在人类缺血诱导的神经元死亡的干预。
Transient global or forebrain ischemia induced experimentally in animals can cause selective, delayed neuronal death of hippocampal CA1 pyramidal neurons. A striking feature is a delayed rise in intracellular free Zn2+ in CA1 neurons just before the onset of histologically detectable cell death. Here we show that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) at Schaffer collateral to CA1 synapses in postischemic hippocampus exhibit properties of Ca2+/Zn2+-permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in Zn2+ and cell death. At 42 h after ischemia, AMPA excitatory postsynaptic currents exhibited pronounced inward rectification and marked sensitivity to 1-naphthyl acetyl spermine (Naspm), a selective channel blocker of GluR2-lacking AMPARs. In control hippocampus, AMPA excitatory postsynaptic currents were electrically linear and relatively insensitive to Naspm. Naspm injected intrahippocampally at 9-40 h after insult greatly reduced the late rise in intracellular free Zn2+ in postischemic CA1 neurons and afforded partial protection against ischemia-induced cell death. These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free Zn2+ and death of CA1 neurons, although a direct action at the time of the rise in Zn2+ is unproven. This receptor subtype appears to be an important therapeutic target for intervention in ischemia-induced neuronal death in humans.