Astrocytes are more resistant than neurons to the cytotoxic effects of increased [Zn2+]i

Increased intracellular free Zn2+ ([Zn2+](i)) is toxic to neurons. Glia are more resistant to Zn2+-mediated toxicity; however, it is not known if this is because glia are less permeable to Zn2+ or if glia possess intrinsic mechanisms that serve to buffer or extrude excess [Zn2+](i). We used the Zn2+-selective ionophore pyrithione to directly increase [Zn2+](i) in both neurons and astrocytes. In neurons, a 5-min exposure to 1 mu M extracellular Zn2+ in combination with pyrithione produced widespread toxicity, whereas extensive astrocyte injury was not observed until extracellular Zn2+ was increased to 10 mu M. Measurements with magfura-2 demonstrated that pyrithione increased [Zn2+](i), to similar levels in both cell types. We also measured how increased [Zn2+](i) affects mitochondrial membrane potential (Delta psi(m)). In astrocytes, but not in neurons, toxic [Zn2+](i) resulted in an acute loss of Delta psi(m) suggesting that mitochondrial dysregulation may be an early event in [Zn2+](i)-induced astrocyte but not neuronal death. (C) 2000 Academic Press.