Abstract
Accumulating evidence has provided a causative role of zinc (Zn2+) in neuronal death following ischemic brain injury. Using a hypoxia model of primary cultured cortical neurons with hypoxia-inducing chemicals, cobalt chloride (1 mM CoCl2), deferoxamine (3 mM DFX), and sodium azide (2 mM NaN3), we evaluated whether Zn2+ is involved in hypoxic neuronal death. The hypoxic chemicals rapidly elicited intracellular Zn2+ release/accumulation in viable neurons. The immediate addition of the Zn2+ chelator, CaEDTA or N,N,N’N’-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), prevented the intracellular Zn2+ load and CoCl2-induced neuronal death, but neither 3 hour later Zn2+ chelation nor a non-Zn2+ chelator ZnEDTA (1 mM) demonstrated any effects. However, neither CaEDTA nor TPEN rescued neurons from cell death following DFX- or NaN3-induced hypoxia, whereas ZnEDTA rendered them resistant to the hypoxic injury. Instead, the immediate supplementation of Zn2+ rescued DFX- and NaN3-induced neuronal death. The iron supplementation also afforded neuroprotection against DFX-induced hypoxic injury. Thus, although intracellular Zn2+ release/accumulation is common during chemical hypoxia, Zn2+ 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.
Highlights
Zinc (Zn2+) contributes to neuronal injury according to various experimental models of excitotoxic brain injury (Sensi et al, 2011)
Since the involvement of Zn2+ in neuronal death in the hippocampal CA1 area following transient global cerebral ischemia was reported (Koh et al, 1996), studies have suggested that excessive Zn2+ release/accumulation leads to neuronal injury after hypoxia/ischemia (Sensi et al, 2011)
When mouse hippocampal slices are subjected to oxygen and glucose deprivation (OGD)—which is a typical experimental model of hypoxia/ischemia—intracellular Zn2+ becomes prominent in degenerating neurons, whereby the Zn2+ chelator CaEDTA attenuates both Zn2+ accumulation and neuronal death (Yin et al, 2002; Medvedeva et al, 2009)
Summary
Zinc (Zn2+) contributes to neuronal injury according to various experimental models of excitotoxic brain injury (Sensi et al, 2011). Intracellular Zn2+ release/accumulation obviously precedes neuronal death in these experimental models (Koh et al, 1996) since Zn2+. Since the involvement of Zn2+ in neuronal death in the hippocampal CA1 area following transient global cerebral ischemia was reported (Koh et al, 1996), studies have suggested that excessive Zn2+ release/accumulation leads to neuronal injury after hypoxia/ischemia (Sensi et al, 2011). When mouse hippocampal slices are subjected to oxygen and glucose deprivation (OGD)—which is a typical experimental model of hypoxia/ischemia—intracellular Zn2+ becomes prominent in degenerating neurons, whereby the Zn2+ chelator CaEDTA attenuates both Zn2+ accumulation and neuronal death (Yin et al, 2002; Medvedeva et al, 2009). Recent studies have provided that Zn2+ promotes hypoxic cell death by upregulating hypoxia-inducible transcription factor-1α (HIF1α) via an activation of NADPH oxidase or poly(ADP-ribose) polymerase (PARP; Pan et al, 2013; Malairaman et al, 2014)
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