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

Abstract

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 µM substantially induced astrocytic cytotoxicity, which also resulted from long-term exposure to 5 µM 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. J. Cell. Biochem. 103: 825–834, 2008.