Extracellular and intracellular glutathione protects astrocytes from Zn2+-induced cell death

Free Zn(2+) is released in excess at excitatory synapses in pathological conditions including transient global and focal cerebral ischemia, which causes neuronal and glial cell death. In the current study, we explored the mechanism underlying Zn(2+)-induced cell death in primary cortical astroglial cultures. Chronic treatment with 30-35 microM Zn(2+) led to the death of 70-95% of astrocytes within 18 h, preceded by Zn(2+) influx. Extracellular glutathione (GSH; 100 microM) completely blocked the Zn(2+) influx and Zn(2+) toxicity. The Zn(2+) toxicity was also inhibited when intracellular GSH was increased. Conversely, it was aggravated when intracellular GSH was depleted by buthionine sulfoximine (BSO). Consistently, the level of cellular GSH was notably decreased with a concurrent increase in oxidized GSH in Zn(2+)-treated astrocytes. These results suggest that the disruption of proper maintenance of thiol homeostasis is a mechanism underlying Zn(2+) toxicity in primary cortical astrocytes.