Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death

Agata Calderone, Teresa Jover, Toshihiro Mashiko, Kyang Min Noh, Hidenobu Tanaka, Michael V.L. Bennett, R. Suzanne Zukin

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

Transient global ischemia induces a delayed rise in intracellular Zn 2+, 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 ∼50% (late CaEDTA) to 75% (early CaEDTA) of animals. We also show that Zn 2+ 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 Zn 2+ 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), p75NTR 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+, p75NTR 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.

Original languageEnglish (US)
Pages (from-to)9903-9913
Number of pages11
JournalJournal of Neuroscience
Volume24
Issue number44
DOIs
StatePublished - Nov 3 2004

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Keywords

  • AMPA receptors
  • Apoptosis
  • Excitotoxicity
  • Global ischemia
  • Neuronal death
  • Zinc
  • p75

ASJC Scopus subject areas

  • Neuroscience(all)

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