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.
Canzoniero
Lorella M T
LM
Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA. canzon@unisannio@it
Manzerra
Pat
P
Sheline
Christian T
CT
Choi
Dennis W
DW
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D018920:Coculture Techniques; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D015032:Zinc / Q000633:toxicity*
D002614:Chelating Agents; D015032:Zinc