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Neuropharmacology. 2003 Sep;45(3):420-8.

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

Author information

1
Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA. canzon@unisannio@it

Abstract

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.

PMID:
12871659
DOI:
10.1016/s0028-3908(03)00171-0
[Indexed for MEDLINE]

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