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The Journal of Neuroscience, October 11, 2006, 26(41):10430-10437; doi:10.1523/JNEUROSCI.1588-06.2006

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Cellular/Molecular
Intracellular Zinc Elevation Measured with a "Calcium-Specific" Indicator during Ischemia and Reperfusion in Rat Hippocampus: A Question on Calcium Overload

Christian J. Stork and Yang V. Li

Department of Biomedical Science, Program in Molecular and Cellular Biology, Ohio University, Athens, Ohio 45701

Correspondence should be addressed to Dr. Yang V. Li, Department of Biomedical Sciences, Ohio University, 346 Irvine Hall, Athens, OH 45701. Email: Li{at}oucom.ohiou.edu

Much of our current evidence concerning of the role of calcium (Ca²⁺) as a second messenger comes from its interaction with fluorescent probes; however, many Ca²⁺ probes also have a higher affinity for another divalent cation: zinc (Zn²⁺). In this study, using a selective Zn²⁺ probe (Newport Green), we investigated the accumulation of intracellular Zn²⁺ transients in acute rat hippocampal slices during ischemia, simulated by oxygen and glucose deprivation (OGD). Subsequent reperfusion with glucose-containing oxygenated medium resulted in an additional increase in intracellular Zn²⁺. Such observations compelled us to investigate the contribution of Zn²⁺ to the alleged intracellular Ca²⁺ overload occurring in ischemia and reperfusion. Using confocal fluorescent microscopy of Calcium Green-1, a widely used Ca²⁺ indicator, we detected increases in fluorescence intensity during OGD and reperfusion. However, application of a Zn²⁺ chelator, at the peak of the fluorescence elevation (interpreted as Ca²⁺ overload), resulted in a significant drop in intensity, suggesting that rising Zn²⁺ is the primary source of the increasing Calcium Green-1 fluorescence. Finally, staining with the cell viability indicator propidium iodide revealed that Zn²⁺ is responsible for the ischemic neuronal cell death, because Zn²⁺ chelation prevented cells from sustaining ischemic damage. Current cellular models of ischemic injury center on Ca²⁺-mediated excitotoxicity. Our results indicate that Zn²⁺ elevation contributes to conventionally recognized Ca²⁺ overload and also suggest that the role of Ca²⁺ in neurotoxicity described previously using Ca²⁺ probes may need to be re-examined to determine whether effect previously attributed to Ca²⁺ could, in part, be attributable to Zn²⁺.

Key words: zinc; calcium; fluorescence; ischemia; nitric oxide; cell death

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Received April 12, 2006; revised Aug. 25, 2006; accepted Aug. 25, 2006.

Correspondence should be addressed to Dr. Yang V. Li, Department of Biomedical Sciences, Ohio University, 346 Irvine Hall, Athens, OH 45701. Email: Li{at}oucom.ohiou.edu

This article has been cited by other articles:

				Y. V. Medvedeva, B. Lin, C. W. Shuttleworth, and J. H. Weiss Intracellular Zn2+ Accumulation Contributes to Synaptic Failure, Mitochondrial Depolarization, and Cell Death in an Acute Slice Oxygen-Glucose Deprivation Model of Ischemia J. Neurosci., January 28, 2009; 29(4): 1105 - 1114. [Abstract] [Full Text] [PDF]

				F. G. De Felice, P. T. Velasco, M. P. Lambert, K. Viola, S. J. Fernandez, S. T. Ferreira, and W. L. Klein Abeta Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine J. Biol. Chem., April 13, 2007; 282(15): 11590 - 11601. [Abstract] [Full Text] [PDF]

eLetters:

Read all eLetters

Zinc has not been ignored

Ian J Reynolds, et al.

J. Neurosci. Online, 13 Nov 2006 [Full text]

A selective calcium indicator is needed. Re: Zinc has not been ignored

Yang V Li

J. Neurosci. Online, 28 Jan 2007 [Full text]

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