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The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease

Abstract

The term spreading depolarization describes a wave in the gray matter of the central nervous system characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression). In the clinic, unequivocal electrophysiological evidence now exists that spreading depolarizations occur abundantly in individuals with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage or traumatic brain injury. Spreading depolarization is induced experimentally by various noxious conditions including chemicals such as potassium, glutamate, inhibitors of the sodium pump, status epilepticus, hypoxia, hypoglycemia and ischemia, but it can can also invade healthy, naive tissue. Resistance vessels respond to it with tone alterations, causing either transient hyperperfusion (physiological hemodynamic response) in healthy tissue or severe hypoperfusion (inverse hemodynamic response, or spreading ischemia) in tissue at risk for progressive damage, which contributes to lesion progression. Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat these neurological conditions.

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Figure 1: Mechanisms of spreading depolarization in the neuron.
Figure 2: Normal (spreading hyperemia) and inverse (spreading ischemia) function of the neurovascular unit in response to spreading depolarization in the human brain.
Figure 3: Spreading ischemia in the rat brain.
Figure 4: Vicious cycle underlying spreading ischemia.

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Acknowledgements

Supported by grants of the Deutsche Forschungsgemeinschaft (DFG DR 323/2-2, 323/3-1, 323/5-1, SFB Tr3 D10), the Bundesministerium für Bildung und Forschung (Center for Stroke Research Berlin, 01 EO 0801), Bernstein Center for Computational Neuroscience Berlin 01GQ1001C B2 and the Kompetenznetz Schlaganfall. I would like to thank C. Reiffurth and S. Major for help with the figures.

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Dreier, J. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17, 439–447 (2011). https://doi.org/10.1038/nm.2333

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