PT  - JOURNAL ARTICLE
AU  - Agata Calderone
AU  - Teresa Jover
AU  - Toshihiro Mashiko
AU  - Kyung-min Noh
AU  - Hidenobu Tanaka
AU  - Michael V. L. Bennett
AU  - R. Suzanne Zukin
TI  - Late Calcium EDTA Rescues Hippocampal CA1 Neurons from Global Ischemia-Induced Death
AID  - 10.1523/JNEUROSCI.1713-04.2004
DP  - 2004 Nov 03
TA  - The Journal of Neuroscience
PG  - 9903--9913
VI  - 24
IP  - 44
4099  - http://www.jneurosci.org/content/24/44/9903.short
4100  - http://www.jneurosci.org/content/24/44/9903.full
SO  - J. Neurosci.2004 Nov 03; 24
AB  - 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), 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.