Inhibition of cadmium-induced oxidative injury in rat primary astrocytes by the addition of antioxidants and the reduction of intracellular calcium

Exposure of the brain to cadmium ions (Cd2+) 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 Cd2+ induced injury compared with cortical neurons and microglia (CNS macrophages). However, treatment with CdCl2 for 24 h at concentrations higher than 20 mu M substantially induced astrocytic cytotoxicity, which also resulted from long-term exposure to 5 mu M of CdCl2. Intracellular calcium levels were found to rapidly increase after the addition of CdCl2 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 Cd2+-treated astrocytes. Adenovirus-mediated transfer of superoxide dismutase (SOD) or glutathione peroxidase (GPx) genes increased survival of Cd2+-exposed astrocytes. In addition, increased ROS generation and astrocytic cell death due to Cd2+ exposure was inhibited when astrocytes were treated with the polyphenolic compound ellagic acid (EA). Taken together, Cd2+ 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 Cd2+-primed astrocytes. This information provides a useful approach for treating Cd2+ induced CNS neurological disorders.