Membrane-permeant chelators can attenuate Zn2+-induced cortical neuronal death

Chelating extracellular Zn(2+) with the membrane-impermeant Zn(2+) chelator, CaEDTA, can inhibit toxic Zn(2+) influx and subsequent neuronal death. However, this drug does not cross the blood-brain barrier. In the present study, we explored the ability of two membrane-permeant Zn(2+) chelators to inhibit Zn(2+)-induced death of cultured cortical neurons. Addition of either the high affinity (K(D)=10(-15.6)) Zn(2+) chelator, N, N, N', N', tetrakis (2-pyridylmethyl) etylenediaminepentaethylene (TPEN), or the low affinity (K(D)=10(-6)) Zn(2+) chelator, 1-hydroxypyridine-2-thione (pyrithione), to the culture medium following exposure to extracellular Zn(2+) reduced subsequent neuronal death, even if chelator administration was delayed by up to 1 h. Indeed, some delay was essential for neuroprotection with pyrithione, as co-administration of pyrithione together with extracellular Zn(2+) increased levels of [Zn(2+)](i) and cell death compared to the levels induced by Zn(2+) alone. TPEN, but not pyrithione, was intrinsically toxic at high concentrations, likely due to excessive chelation of [Zn(2+)](i), as this intrinsic toxicity was reduced by prior addition of extracellular Zn(2+). These data point to a potential therapeutic role for membrane-permeant Zn(2+) chelators, perhaps especially possessing low Zn(2+) affinity, in attenuating neuronal death after certain acute insults.