Ionic Regulation of Cell Volume Changes and Cell Death after Ischemic Stroke
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ORIGINAL ARTICLE
Ionic Regulation of Cell Volume Changes and Cell Death after Ischemic Stroke Mingke Song & Shan Ping Yu
Received: 2 September 2013 / Revised: 16 October 2013 / Accepted: 19 November 2013 # Springer Science+Business Media New York 2013
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. Keywords Stroke . Ionic mechanism . Potassium channels . Na+/K+-ATPase . Sodium pump . Hybrid cell death . Cell volume regulation M. Song : S. P. Yu (*) Department of Anesthesiology, Emory University School of Medicine, 101 Woodruff Circle, WMB Building Suite 620, Atlanta, GA 30322, USA e-mail: [email protected]
Introduction According to the American Heart Association (AHA) 2013 updated statistics [1], about 795,000 people experience a new or recurrent stroke each year in the United States. This makes stroke one of the leading causes of human death and long-term disability in the USA. Similar stroke occurrence and threats to human life and health are seen in other countries. The economic and social burden of stroke is severe in the USA and around the world. Brain ischemia initially causes oxygen and glucose deprivation and relatively acute (from hours to the first 1–3 days) cell death in the region where cerebral blood flow is arrested or severely reduced (≥80 % decrease from the baseline level), eventually leading to an infarction core during this time [2]. The remaining tissue within the peri-infarct region (also known as the penumbra) is partially and chronically (days to weeks) in
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