Disparate roles of zinc in chemical hypoxia-induced neuronal death

摘要

Accumulating evidence has provided a causative role of zinc (Zn~(2+)) in neuronal death following ischemic brain injury. Using a hypoxia model of primary cultured cortical neurons with hypoxia-inducing chemicals, cobalt chloride (1 mM CoCl_(2)), deferoxamine (3 mM DFX), and sodium azide (2 mM NaN_(3)), we evaluated whether Zn~(2+)is involved in hypoxic neuronal death. The hypoxic chemicals rapidly elicited intracellular Zn~(2+)release/accumulation in viable neurons. The immediate addition of the Zn~(2+)chelator, CaEDTA or N,N,N’N’-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), prevented the intracellular Zn~(2+)load and CoCl_(2)-induced neuronal death, but neither 3 hour later Zn~(2+)chelation nor a non-Zn~(2+)chelator ZnEDTA (1 mM) demonstrated any effects. However, neither CaEDTA nor TPEN rescued neurons from cell death following DFX- or NaN_(3)-induced hypoxia, whereas ZnEDTA rendered them resistant to the hypoxic injury. Instead, the immediate supplementation of Zn~(2+)rescued DFX- and NaN_(3)-induced neuronal death. The iron supplementation also afforded neuroprotection against DFX-induced hypoxic injury. Thus, although intracellular Zn~(2+)release/accumulation is common during chemical hypoxia, Zn~(2+)might differently influence the subsequent fate of neurons; it appears to play a neurotoxic or neuroprotective role depending on the hypoxic chemical used. These results also suggest that different hypoxic chemicals may induce neuronal death via distinct mechanisms.