Cadmium-induced astroglial death proceeds via glutathione depletion

Cadmium is a heavy metal that accumulates in the body, and its accumulation in the brain damages both neurons and glial cells. In the current study, we explored the mechanism underlying cadmium toxicity in primary cortical astroglia cultures. Chronic treatment with 10 microM cadmium was sufficient to cause 90% cell death in 18 hr. However, unlike that observed in neurons, cadmium-induced astroglial toxicity was not attenuated by the antioxidants trolox (100 microM), caffeic acid (1 mM), and vitamin C (1 mM). In contrast, extracellular 100 microM glutathione (GSH; gamma-Glu-Cys-Gly) or 100 microM cysteine almost completely blocked cadmium-induced astroglial death, whereas 300 microM oxidized GSH (GSSG) or 300 microM cystine, which do not have the free thiol group, were ineffective. In addition, cadmium toxicity was noticeably inhibited or enhanced when intracellular GSH was, respectively, increased by using the cell-permeable glutathione ethyl ester (GSH-EE) or depleted by using buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. In agreement with these data, intracellular GSH levels were found to be depressed in cadmium-treated astrocytes. These results suggest that the toxic effect of cadmium on primary astroglial cells involves GSH depletion and, furthermore, that GSH administration can potentially be used to counteract cadmium-induced astroglial cell death therapeutically.