Late Calcium EDTA Rescues Hippocampal CA1 Neurons from Global Ischemia-Induced Death
抄録
<jats:p>Transient global ischemia induces a delayed rise in intracellular Zn<jats:sup>2+</jats:sup>, 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 Zn<jats:sup>2+</jats:sup>toxicity<jats:italic>in vivo</jats:italic>are not well delineated. Here we show the striking finding that intraventricular injection of the high-affinity Zn<jats:sup>2+</jats:sup>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 ∼50% (late CaEDTA) to 75% (early CaEDTA) of animals. We also show that Zn<jats:sup>2+</jats:sup>acts via temporally distinct mechanisms to promote neuronal death. Early CaEDTA attenuated ischemia-induced GluR2 mRNA and protein downregulation (and, by inference, formation of Zn<jats:sup>2+</jats:sup>-permeable AMPARs), the delayed rise in Zn<jats:sup>2+</jats:sup>, and neuronal death. These findings suggest that Zn<jats:sup>2+</jats:sup>acts at step(s) upstream from GluR2 gene downregulation and implicate Zn<jats:sup>2+</jats:sup>in transcriptional regulation and/or GluR2 mRNA stability. Early CaEDTA also blocked mitochondrial release of cytochrome<jats:italic>c</jats:italic>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<jats:sup>NTR</jats:sup>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 Zn<jats:sup>2+</jats:sup>, p75<jats:sup>NTR</jats:sup>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.</jats:p>
収録刊行物
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- The Journal of Neuroscience
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The Journal of Neuroscience 24 (44), 9903-9913, 2004-11-03
Society for Neuroscience
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詳細情報 詳細情報について
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- CRID
- 1363107369781815040
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- NII論文ID
- 30010124115
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- ISSN
- 15292401
- 02706474
- http://id.crossref.org/issn/02706474
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- データソース種別
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- Crossref
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