The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention

Overview

Journal Neurocrit Care

Specialty Critical Care

Date 2022 Mar 8

PMID 35257321

Authors

R David Andrew

Jed A Hartings

Cenk Ayata

K C Brennan

Ken D Dawson-Scully

Eszter Farkas

Oscar Herreras

Sergei A Kirov

Michael Muller

Nikita Ollen-Bittle

Clemens Reiffurth

Omer Revah

R Meldrum Robertson

C William Shuttleworth

Ghanim Ullah

Jens P Dreier

Affiliations

Soon will be listed here.

Abstract

Background: When 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.

Methods: In 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.

Results: We 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.

Conclusions: Finally, 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.

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