Yang Chung-Shi, Tzou Bo-Cheng, Liu Yu-Peng, Tsai May-Jywan, Shyue Song-Kun, Tzeng Shun-Fen
Center for Nanomedicine Research, National Health Research Institutes, Zhunan, Taiwan, ROC.
J Cell Biochem. 2008 Feb 15;103(3):825-34. doi: 10.1002/jcb.21452.
Exposure of the brain to cadmium ions (Cd(2+)) is believed to lead to neurological disorders of the central nervous system (CNS). In this study, we tested the hypothesis that astrocytes, the major CNS-supporting cells, are resistant to Cd(2+)-induced injury compared with cortical neurons and microglia (CNS macrophages). However, treatment with CdCl(2) for 24 h at concentrations higher than 20 microM substantially induced astrocytic cytotoxicity, which also resulted from long-term exposure to 5 microM of CdCl(2). Intracellular calcium levels were found to rapidly increase after the addition of CdCl(2) into astrocytes, which led to a rise in reactive oxygen species (ROS) and to mitochondrial impairment. In accordance, preexposure to the extracellular calcium chelator EGTA effectively reduced ROS production and increased survival of Cd(2+)-treated astrocytes. Adenovirus-mediated transfer of superoxide dismutase (SOD) or glutathione peroxidase (GPx) genes increased survival of Cd(2+)-exposed astrocytes. In addition, increased ROS generation and astrocytic cell death due to Cd(2+) exposure was inhibited when astrocytes were treated with the polyphenolic compound ellagic acid (EA). Taken together, Cd(2+)-induced astrocytic cell death resulted from disrupted calcium homeostasis and an increase in ROS. Moreover, our findings demonstrate that enhancement of the activity of intracellular antioxidant enzymes and supplementation with a phenolic compound, a natural antioxidant, improves survival of Cd(2+)-primed astrocytes. This information provides a useful approach for treating Cd(2+)-induced CNS neurological disorders.
大脑暴露于镉离子（Cd(2+)）被认为会导致中枢神经系统（CNS）的神经紊乱。在本研究中，我们验证了这样一个假设：作为中枢神经系统主要支持细胞的星形胶质细胞，与皮质神经元和小胶质细胞（中枢神经系统巨噬细胞）相比，对Cd(2+)诱导的损伤具有抗性。然而，用浓度高于20 microM的CdCl(2)处理24小时会显著诱导星形胶质细胞的细胞毒性，长期暴露于5 microM的CdCl(2)也会导致这种情况。在向星形胶质细胞中添加CdCl(2)后，发现细胞内钙水平迅速升高，这导致活性氧（ROS）增加和线粒体损伤。相应地，预先暴露于细胞外钙螯合剂EGTA可有效减少ROS产生，并提高经Cd(2+)处理的星形胶质细胞的存活率。腺病毒介导的超氧化物歧化酶（SOD）或谷胱甘肽过氧化物酶（GPx）基因转移可提高经Cd(2+)处理的星形胶质细胞的存活率。此外，当用多酚化合物鞣花酸（EA）处理星形胶质细胞时，Cd(2+)暴露引起的ROS生成增加和星形胶质细胞死亡受到抑制。综上所述，Cd(2+)诱导的星形胶质细胞死亡是由钙稳态破坏和ROS增加所致。此外，我们的研究结果表明，增强细胞内抗氧化酶的活性以及补充酚类化合物（一种天然抗氧化剂）可提高经Cd(2+)处理的星形胶质细胞的存活率。这些信息为治疗Cd(2+)诱导的中枢神经系统神经紊乱提供了一种有用的方法。
