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 μM extracellular Zn²⁺ in combination with pyrithione produced widespread toxicity, whereas extensive astrocyte injury was not observed until extracellular Zn²⁺ was increased to 10 μM. Measurements with magfura-2 demonstrated that pyrithione increased [Zn²⁺](i) to similar levels in both cell types. We also measured how increased [Zn²⁺](i) effects mitochondrial membrane potential (ΔΨ(m)). In astrocytes, but not in neurons, toxic [Zn²⁺](i) resulted in an acute loss of ΔΨ(m), suggesting that mitochondrial dysregulation may be an early event in [Zn²⁺](i)-induced estrocyte but not neuronal death. (C) 2000 Academic Press.