Abstract
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 µM substantially induced astrocytic cytotoxicity, which also resulted from long‐term exposure to 5 µM 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. J. Cell. Biochem. 103: 825–834, 2008. © 2007 Wiley‐Liss, Inc.