MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity
MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity
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DOI：
10.1523/jneurosci.4948-05.2006
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发表时间：
2006-02-08
影响因子：
5.3
通讯作者：
Nakabeppu, Y
中科院分区：
文献类型：
--
作者：
Kajitani, K;Yamaguchi, H;Nakabeppu, Y
增强的氧化应激与中枢神经系统的兴奋性毒性有关，8-氧-7,8-二氢鸟嘌呤（8-oxoG）是一种主要的核酸氧化损伤，据报道，在给药后大鼠海马中积累。本研究显示，给药后6-12小时，小鼠海马CA3亚区线粒体DNA和细胞RNA中的8-oxoG水平显著升高，但几天后又恢复到基础水平。激光扫描共聚焦显微镜显示，在CA3小胶质细胞中，线粒体DNA中有明显的8-oxoG积累，而在CA3锥体细胞和星形胶质细胞中，核DNA或细胞RNA中也有8-oxoG积累。8-oxoG在细胞DNA或RNA中的积累应该被具有8-oxo-dGTPase （8-oxo-7,8-二氢-2'-脱氧鸟苷三磷酸酶）活性的MutT同源物1 （MTH1）和具有8-oxoG-DNA糖基酶活性的8-oxoG-DNA糖基酶1 （OGG1）抑制。因此，我们检测了海碱盐给药后小鼠海马中MTH1和OGG1的表达水平。kainate给药后，Mth1 mRNA水平很快下降，然后迅速恢复到基础水平以上，Mth1蛋白水平持续升高，而Ogg1 mRNA水平保持不变。kainate给药后，mth1缺失小鼠和野生型小鼠表现出相似程度的CA3神经元丢失；然而，与野生型小鼠相比，MTH1缺失小鼠CA3小胶质细胞线粒体DNA和细胞RNA中积累的8-oxoG水平显著增加，这表明MTH1有效抑制海马细胞DNA和RNA中8-oxoG的积累，特别是在小胶质细胞中，这是由兴奋毒性引起的。
Enhanced oxidative stress has been implicated in the excitotoxicity of the CNS, and 8-oxo-7,8-dihydro-guanine (8-oxoG), a major type of oxidative damage in nucleic acids, was reported to be accumulated in the rat hippocampus after kainate administration. We herein showed that the 8-oxoG levels in mitochondrial DNA and cellular RNA increased significantly in the CA3 subregion of the mouse hippocampus 6-12 h after kainate administration but returned to basal levels within a few days. Laser-scanning confocal microscopy revealed the 8-oxoG accumulation in mitochondrial DNA to be remarkable in CA3 microglia, whereas that in nuclear DNA or cellular RNA was also detected in the CA3 pyramidal cells and astrocytes. 8-oxoG accumulation in cellular DNA or RNA should be suppressed by MutT homolog 1 (MTH1) with 8-oxo-dGTPase (8-oxo-7,8-dihydro-2'-deoxyguanosine triphosphatase) activity and 8-oxoG-DNA glycosylase 1 (OGG1) with 8-oxoG DNA glycosylase activity. We thus examined the expression level of MTH1 and OGG1 in the mouse hippocampus after kainate administration. The Mth1 mRNA level decreased soon after kainate administration and then quickly recovered beyond the basal level, and a continuously increased MTH1 protein level was observed, whereas the Ogg1 mRNA level remained constant. MTH1-null and wild-type mice exhibited a similar degree of CA3 neuron loss after kainate administration; however, the 8-oxoG levels that accumulated in mitochondrial DNA and cellular RNA in the CA3 microglia significantly increased in the MTH1-null mice in comparison with wild-type mice, thus demonstrating that MTH1 efficiently suppresses the accumulation of 8-oxoG in both cellular DNA and RNA in the hippocampus, especially in microglia, caused by excitotoxicity.