Evidence map›Paper›PMID 35194729›Full record

ArticleNeurocritical care2022

Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization.

R David Andrew, Eszter Farkas, Jed A Hartings, K C Brennan, Oscar Herreras, Michael Müller, Sergei A Kirov, Cenk Ayata, Nikita Ollen-Bittle, Clemens Reiffurth and 5 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurocritical care, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.

0numbers the graph read from it
0cells of the map it votes in
31citing papers in PubMed
5.4field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

31 citing papers in PubMed, 49 citations in OpenAlex.

  1. Article
  2. Observational
  3. Thirty years later: Revisiting the glial failure hypothesis as the homeostatic organizing principle of ischemic injury.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026
    Review
  4. Article
  5. Spreading depolarization: A wave that precedes and drives cerebral ischemic cell death-Target for neuroprotection.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026
    Review
  6. Review
  7. Review
  8. Review
  9. Article
  10. Review
  11. Article
  12. Review
  13. Article
  14. Article
  15. Article
  16. Review
  17. Review
  18. Review
  19. Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 14 institutions in 5 countries.

R David AndrewQueen's University, Kingston, ON, Canada. andrewd@queensu.ca.ORCID 0000-0002-4857-7314
Eszter FarkasHungarian Centre of Excellence for Molecular Medicine-University of Szeged, Cerebral Blood Flow and Metabolism Research Group, Department of Cell Biology and Molecular Medicine, University of Szeged, Szeged, Hungary.
Jed A HartingsUniversity of Cincinnati, Cincinnati, OH, USA.
K C BrennanThe University of Utah, Salt Lake City, UT, USA.
Oscar HerrerasInstituto de Neurobiologia Ramon y Cajal, Madrid, Spain.
Michael MüllerUniversity of Göttingen, Göttingen, Germany.
Sergei A KirovMedical College of Georgia, Augusta, GA, USA.
Cenk AyataHarvard Medical School, Harvard University, Boston, MA, USA.
Nikita Ollen-BittleUniversity of Western Ontario, London, ON, Canada.
Clemens ReiffurthCenter for Stroke Research Berlin, Berlin, Germany.
Omer RevahSchool of Medicine, Stanford University, Stanford, CA, USA.
R Meldrum RobertsonQueen's University, Kingston, ON, Canada.
Ken D Dawson-ScullyFlorida Atlantic University, Boca Raton, FL, USA.
Ghanim UllahUniversity of South Florida, Tampa, FL, USA.
Jens P DreierCenter for Stroke Research Berlin, Berlin, Germany.
Queen's University · CAAugusta University · USCharité - Universitätsmedizin Berlin · DEFlorida Atlantic University · USHarvard University · USHumboldt-Universität zu Berlin · DEInstituto Cajal · ESStanford University · USUniversity of Cincinnati · USUniversity of Göttingen · DEUniversity of South Florida · USUniversity of Szeged · HUUniversity of Utah · USWestern University · CA

Funding

Synaptic Circuitry in StrokeR01NS083858 · NINDS · AUGUSTA UNIVERSITY · PI KIROV, SERGEI A · 2014 to 2022
$2.7M
NINDS NIH HHS R01 NS083858
6 · The paper itself

Abstract

backgroundWithin 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury. Yet most neuroscientists assume that the course of early brain injury can be explained by glutamate excitotoxicity, the concept that immediate glutamate release promotes early and downstream brain injury. There are many problems with glutamate release being the unseen culprit, the most practical being that the concept has yielded zero therapeutics over the past 30 years. But the basic science is also flawed, arising from dubious foundational observations beginning in the 1950s

methodsLiterature pertaining to excitotoxicity and to SD over the past 60 years is critiqued.

resultsExcitotoxicity theory centers on the immediate and excessive release of glutamate with resulting neuronal hyperexcitation. This instigates poststroke cascades with subsequent secondary neuronal injury. By contrast, SD theory argues that although SD evokes some brief glutamate release, acute neuronal damage and the subsequent cascade of injury to neurons are elicited by the metabolic stress of SD, not by excessive glutamate release. The challenge we present here is to find new clinical targets based on more informed basic science. This is motivated by the continuing failure by neuroscientists and by industry to develop drugs that can reduce brain injury following ischemic stroke, traumatic brain injury, or sudden cardiac arrest. One important step is to recognize that SD plays a central role in promoting early neuronal damage. We argue that uncovering the molecular biology of SD initiation and propagation is essential because ischemic neurons are usually not acutely injured unless SD propagates through them. The role of glutamate excitotoxicity theory and how it has shaped SD research is then addressed, followed by a critique of its fading relevance to the study of brain injury.

conclusionsSpreading depolarizations better account for the acute neuronal injury arising from brain ischemia than does the early and excessive release of glutamate.

Indexed as

Brain InjuriesBrain IschemiaCortical Spreading DepressionBrainGlutamic AcidHumansIschemiaGlutamic AcidAlzheimer diseaseAmyotrophic lateral sclerosisBrain swellingConcussionDendritic beadingHuntington diseaseIschemiaKetamineMigraineModelingNa+/K+ pumpPenumbraPersistent vegetative stateStrokeSudden cardiac arrestTraumatic brain injury

Identifiers

PMID35194729
PMCPMC9259542
OpenAlexW4213427679

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.