Abstract
BackgroundWhen a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD.MethodsIn this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na+/K+ pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate.ResultsWe discuss how SD has been investigated with various pitfalls in numerous experimental preparations, how overtaxing the Na+/K+ ATPase elicits SD. Elevated K+ or glutamate are unlikely natural activators of SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling.ConclusionsFinally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as compared with SD theory.
Highlights
Spreading Depolarizations and Their Clinical Importance At the immediate onset of brain ischemia, spreading depolarization (SD) is the principal mechanism ofThis article is part of the collection “Spreading Cortical Depolarization”.electrochemical membrane failure and neuronal swelling in gray matter of the higher brain [1–6]
Within 1–2 min of severe ischemia, depletion of the available adenosine triphosphate (ATP) pool leads to Na+/K+ pump failure with eruption of a front of cellular depolarization that propagates at 1–9 mm/minute throughout the ischemic tissue as well as into the surrounding penumbral and normal tissue [7–11]
SD is associated with a range of diseases and conditions, including migraine-associated aura, concussion [12], traumatic brain injury (TBI), subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, circulatory arrest (Fig. 2), brain death prior to circulatory collapse, and sudden unexplained death in epilepsy [3, 13–18]
Summary
We introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na+/K+ pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate
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