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Ionic Regulation of Cell Volume Changes and Cell Death after Ischemic Stroke

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Abstract

Stroke is a leading cause of human death and disability in the USA and around the world. Shortly after the cerebral ischemia, cell swelling is the earliest morphological change in injured neuronal, glial, and endothelial cells. Cytotoxic swelling directly results from increased Na+ (with H2O) and Ca2+ influx into cells via ionic mechanisms evoked by membrane depolarization and a number of harmful factors such as glutamate accumulation and the production of oxygen reactive species. During the sub-acute and chronic phases after ischemia, injured cells may show a phenotype of cell shrinkage due to complex processes involving membrane receptors/channels and programmed cell death signals. This review will introduce some progress in the understanding of the regulation of pathological cell volume changes and the involved receptors and channels, including NMDA and AMPA receptors, acid-sensing ion channels, hemichannels, transient receptor potential channels, and KCNQ channels. Moreover, accumulating evidence supports a key role of energy deficiency and dysfunction of Na+/K+-ATPase in ischemia-induced cell volume changes and cell death. Specifically, the Na+ pump failure is a prerequisite for disruption of ionic homeostasis including a pro-apoptotic disruption of the K+ homeostasis. Finally, we will introduce the concept of hybrid cell death as a result of the Na+ pump failure in cultured cells and the ischemic brain. The goal of this review is to outline recent understanding of the ionic mechanism of ischemic cytotoxicity and suggest innovative ideas for future translational research.

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Acknowledgments

This work was supported by NIH grant NS057255, the American Heart Association (AHA) Grant-in-Aid Award GRNT12060222, and AHA Postdoctoral Fellowship (POST12080252).

Compliance with Ethics Requirements

This is a review article that does not contain any studies with human or animal subjects. The authors assume that all original studies cited in this review followed institutional and national guidelines for the care and use of laboratory animals and guidelines for clinical trials on patients. However, the authors are not responsible for any violation of the guidelines in the original investigations.

Conflict of Interest

The two authors receive research grants from NIH and AHA as listed below.

Shan Ping Yu: NIH grant NS057255, the American Heart Association (AHA) Grant-in-Aid Award GRNT12060222.

Mingke Song: AHA Postdoctoral Fellowship (POST12080252).

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  1. Department of Anesthesiology, Emory University School of Medicine, 101 Woodruff Circle, WMB Building Suite 620, Atlanta, GA, 30322, USA

    Mingke Song & Shan Ping Yu

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  1. Mingke Song
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  2. Shan Ping Yu
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Correspondence to Shan Ping Yu.

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Song, M., Yu, S.P. Ionic Regulation of Cell Volume Changes and Cell Death after Ischemic Stroke. Transl. Stroke Res. 5, 17–27 (2014). https://doi.org/10.1007/s12975-013-0314-x

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  • DOI: https://doi.org/10.1007/s12975-013-0314-x

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