期刊
JOURNAL OF NEUROSCIENCE
卷 24, 期 44, 页码 9903-9913出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1713-04.2004
关键词
zinc; global ischemia; neuronal death; apoptosis; excitotoxicity; AMPA receptors; p75(NTR)
资金
- NINDS NIH HHS [NS45287, R01 NS046742, NS46742, R01 NS020752, NS20752, R01 NS045287] Funding Source: Medline
Transient global ischemia induces a delayed rise in intracellular Zn2+, which may be mediated via glutamate receptor 2 (GluR2)-lacking AMPA receptors (AMPARs), and selective, delayed death of hippocampal CA1 neurons. The molecular mechanisms underlying Zn2+ toxicity in vivo are not well delineated. Here we show the striking finding that intraventricular injection of the high-affinity Zn2+ chelator calcium EDTA (CaEDTA) at 30 min before ischemia ( early CaEDTA) or at 48 - 60 hr ( late CaEDTA), but not 3 - 6 hr, after ischemia, afforded robust protection of CA1 neurons in similar to 50% ( late CaEDTA) to 75% ( early CaEDTA) of animals. We also show that Zn2+ acts via temporally distinct mechanisms to promote neuronal death. Early CaEDTA attenuated ischemia-induced GluR2 mRNA and protein downregulation ( and, by inference, formation of Zn2+-permeable AMPARs), the delayed rise in Zn2+, and neuronal death. These findings suggest that Zn2+ acts at step(s) upstream from GluR2 gene downregulation and implicate Zn2+ in transcriptional regulation and/or GluR2 mRNA stability. Early CaEDTA also blocked mitochondrial release of cytochrome c and Smac/DIABLO ( second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with low pI), caspase-3 activity ( but not procaspase-3 cleavage), p75(NTR) induction, and DNA fragmentation. These findings indicate that CaEDTA preserves the functional integrity of the mitochondrial outer membrane and arrests the caspase death cascade. Late injection of CaEDTA at a time when GluR2 is downregulated and caspase is activated inhibited the delayed rise in Zn2+, p75(NTR) induction, DNA fragmentation, and cell death. The finding of neuroprotection by late CaEDTA administration has striking implications for intervention in the delayed neuronal death associated with global ischemia.
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