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The Journal of Neuroscience, November 3, 2004, 24(44):9903-9913; doi:10.1523/JNEUROSCI.1713-04.2004

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Neurobiology of Disease
Late Calcium EDTA Rescues Hippocampal CA1 Neurons from Global Ischemia-Induced Death

Agata Calderone, Teresa Jover, ^* Toshihiro Mashiko, ^* Kyung-min Noh, Hidenobu Tanaka,  Michael V. L. Bennett, and R. Suzanne Zukin

Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

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 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.

Key words: zinc; global ischemia; neuronal death; apoptosis; excitotoxicity; AMPA receptors; p75^NTR

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Received May 4, 2004; revised September 15, 2004; accepted September 16, 2004.

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