Induced tolerance to glutamate neurotoxicity through down‐regulation of NR2 subunits of N‐methyl‐D‐aspartate receptors in cultured rat striatal neurons
Induced tolerance to glutamate neurotoxicity through down‐regulation of NR2 subunits of N‐methyl‐D‐aspartate receptors in cultured rat striatal neurons
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DOI：
10.1002/jnr.22388
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发表时间：
2010-08
影响因子：
4.2
通讯作者：
Y. Kambe;N. Nakamichi;T. Takarada;R. Fukumori;Y. Yoneda
中科院分区：
文献类型：
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作者：
Y. Kambe;N. Nakamichi;T. Takarada;R. Fukumori;Y. Yoneda
我们之前已经在培养的大鼠皮层和大鼠海马神经元之间显示了对N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）介导的谷氨酸（Glu）兴奋性毒性的差异脆弱性。在这项研究中，我们评估了可能诱导耐受NMDA神经毒性在培养的大鼠纹状体神经元与先前持续激活的NMDAR。短暂暴露于Glu或NMDA 1小时导致细胞活力显着下降，确定24小时后，在培养的大鼠纹状体神经元，而没有显着的损失被视为细胞存活后暴露于Glu或NMDA在纹状体神经元先前培养的Glu或NMDA。持续培养与Glu或NMDA总是导致NR 2的蛋白质水平显着下降，但不NR 1，亚基不影响其mRNA水平。在海马神经元中，以对NMDAR拮抗剂敏感的方式观察到对NMDA兴奋毒性的类似诱导耐受。在纹状体神经元中加入NMDA后，先前培养的NMDA诱导细胞内游离Ca 2+水平和线粒体膜电位的变化不太有效。然而，钙蛋白酶抑制剂-I显著阻止了NMDA培养的纹状体神经元中NR 2B和NR 2C蛋白水平的降低。这些结果表明，NMDAR的预先紧张性激活将通过与钙蛋白酶诱导的大鼠纹状体神经元中特定NR 2亚基下调相关的机制诱导对NMDAR介导的兴奋性毒性的耐受。© 2010 Wiley利斯公司
We have previously shown differential vulnerabilities to glutamate (Glu) excitotoxicity mediated by the N‐methyl‐D‐aspartate (NMDA) receptor (NMDAR) between rat cortical and rat hippocampal neurons in culture. In this study, we evaluated the possible induced tolerance to NMDA neurotoxicity in cultured rat striatal neurons with prior sustained activation of NMDAR. Brief exposure to Glu or NMDA for 1 hr led to a significant decrease in cellular vitality determined 24 hr later in cultured rat striatal neurons, whereas no marked loss was seen in cellular survival after exposure to Glu or NMDA in striatal neurons previously cultured with Glu or NMDA. Sustained culture with Glu or NMDA invariably led to a significant decrease in protein levels of NR2, but not NR1, subunits without affecting their mRNA levels. Similar induced tolerance was seen to the excitotoxicity of NMDA in hippocampal neurons in a manner sensitive to an NMDAR antagonist. Prior culture with NMDA induced less effective alterations in both intracellular free Ca2+ levels and mitochondrial membrane potentials after the addition of NMDA in striatal neurons. However, calpain inhibitor‐I significantly prevented the decreased NR2B and NR2C protein levels in striatal neurons cultured with NMDA. These results suggest that prior tonic activation of NMDAR would induce tolerance to the excitotoxicity mediated by NMDAR through a mechanism related to calpain‐induced down‐regulation of particular NR2 subunits in rat striatal neurons. © 2010 Wiley‐Liss, Inc.