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

Chelating extracellular Zn2+ with the membrane-impermeant Zn2+ chelator, CaEDTA, can inhibit toxic Zn2+ 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 Zn2+ chelators to inhibit Zn2+-induced death of cultured cortical neurons. Addition of either the high affinity (K-D = 10(-15.6)) Zn2+ chelator, N, N, N', N', tetrakis (2-pyridylmethyl) etylenediaminepentaethylene (TPEN), or the low affinity (K-D, = 10(-6)) Zn2+ chelator, 1-hydroxypyridine-2-thione (pyrithione), to the culture medium following exposure to extracellular Zn2+ 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 to-ether with extracellular Zn2+ increased levels of [Zn2+](i) and cell death compared to the levels induced by Zn2+ alone. TPEN, but not pyrithione, was intrinsically toxic at high concentrations, likely due to excessive chelation of [Zn2+](i), as this intrinsic toxicity was reduced by prior addition of extracellular Zn2+. These data point to a potential therapeutic role for membrane-permeant Zn2+ chelators, perhaps especially possessing low Zn2+ affinity, in attenuating neuronal death after certain acute insults. (C) 2003 Published by Elsevier Science Ltd.