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Spreading depolarization: A wave that precedes and drives cerebral ischemic cell death-Target for neuroprotection.

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Title: Spreading depolarization: A wave that precedes and drives cerebral ischemic cell death-Target for neuroprotection.
Authors: Pensato U; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.; Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy., Ospel JM; Department of Radiology, University of Calgary, Calgary, AB, Canada., Lemale CL; Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Hartings JA; Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Romoli M; Department of Neurosciences, Bufalini Hospital, Cesena, Italy., Sacco S; Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy., Dreier JP; Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Department of Neurology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Bernstein Center for Computational Neuroscience Berlin, Berlin, Germany.; Einstein Center for Neurosciences Berlin, Berlin, Germany.
Source: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [J Cereb Blood Flow Metab] 2026 Jul; Vol. 46 (7), pp. 1759-1781. Date of Electronic Publication: 2026 Mar 21.
Publication Type: Journal Article; Review; Research Support, Non-U.S. Gov't
Language: English
Journal Info: Publisher: SAGE Publications Country of Publication: United States NLM ID: 8112566 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-7016 (Electronic) Linking ISSN: 0271678X NLM ISO Abbreviation: J Cereb Blood Flow Metab Subsets: MEDLINE
Imprint Name(s): Publication: 2016- : Thousand Oaks, CA : SAGE Publications
Original Publication: New York : Raven Press, c1981-
MeSH Terms: Brain Ischemia*/physiopathology , Brain Ischemia*/pathology , Cell Death*/physiology , Cortical Spreading Depression*/physiology , Neuroprotection*/physiology, Neurons/pathology ; Humans ; Animals
Abstract: Spreading depolarization (SD) is an all-or-none response of gray matter, evolutionarily conserved from insects to mammals and characterized by near-complete breakdown of transmembrane ion gradients and cytotoxic edema. In humans, SD has been recorded in diverse neurological conditions, including cerebral ischemia and hemorrhage, traumatic brain injury (TBI), and even during whole-brain death following cardiac arrest or during continued systemic circulation. During migraine aura, initial hyperemia accompanies short-lived and benign SD. SD under energy deficiency is also initially reversible. However, if intraneuronal Ca2+ increases persist for too long, cell death develops, characterized by a negative ultraslow potential. The same SD wave can be long-lasting and deadly in one place, but short and harmless in another. Energy depletion after arterial obstruction triggers SD within minutes, but SD can also arise in non-ischemic tissue and trigger vasoconstriction and ischemia as a result of an inverse hemodynamic response. Overall, SD may be both adaptive and maladaptive, depending on the tissue conditions. As final reversible stage before ischemic neuronal death, it is not only an orderly retreat from life, but can also allow a reboot. SD is a biomarker of neuronal injury during neurocritical care and a compelling yet complex therapeutic target for neuroprotection.
Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Contributed Indexing: Keywords: Ischemic stroke; cardiac arrest; cerebral infarction; cerebral ischemic injury; neuroprotection; spreading depression
Entry Date(s): Date Created: 20260321 Date Completed: 20260701 Latest Revision: 20260915
Update Code: 20260915
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  Label: MeSH Terms
  Group: Su
  Data: <searchLink fieldCode="MM" term="%22Brain+Ischemia%22">Brain Ischemia*</searchLink>/<searchLink fieldCode="MM" term="%22Brain+Ischemia+physiopathology%22">physiopathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Brain+Ischemia%22">Brain Ischemia*</searchLink>/<searchLink fieldCode="MM" term="%22Brain+Ischemia+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Cell+Death%22">Cell Death*</searchLink>/<searchLink fieldCode="MM" term="%22Cell+Death+physiology%22">physiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Cortical+Spreading+Depression%22">Cortical Spreading Depression*</searchLink>/<searchLink fieldCode="MM" term="%22Cortical+Spreading+Depression+physiology%22">physiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Neuroprotection%22">Neuroprotection*</searchLink>/<searchLink fieldCode="MM" term="%22Neuroprotection+physiology%22">physiology</searchLink><br /><searchLink fieldCode="MH" term="%22Neurons%22">Neurons</searchLink>/<searchLink fieldCode="MH" term="%22Neurons+pathology%22">pathology</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Spreading depolarization (SD) is an all-or-none response of gray matter, evolutionarily conserved from insects to mammals and characterized by near-complete breakdown of transmembrane ion gradients and cytotoxic edema. In humans, SD has been recorded in diverse neurological conditions, including cerebral ischemia and hemorrhage, traumatic brain injury (TBI), and even during whole-brain death following cardiac arrest or during continued systemic circulation. During migraine aura, initial hyperemia accompanies short-lived and benign SD. SD under energy deficiency is also initially reversible. However, if intraneuronal Ca<superscript>2+</superscript> increases persist for too long, cell death develops, characterized by a negative ultraslow potential. The same SD wave can be long-lasting and deadly in one place, but short and harmless in another. Energy depletion after arterial obstruction triggers SD within minutes, but SD can also arise in non-ischemic tissue and trigger vasoconstriction and ischemia as a result of an inverse hemodynamic response. Overall, SD may be both adaptive and maladaptive, depending on the tissue conditions. As final reversible stage before ischemic neuronal death, it is not only an orderly retreat from life, but can also allow a reboot. SD is a biomarker of neuronal injury during neurocritical care and a compelling yet complex therapeutic target for neuroprotection.
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
– Name: Ref
  Label: References
  Group: RefInfo
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  Data: <i>Keywords: </i>Ischemic stroke; cardiac arrest; cerebral infarction; cerebral ischemic injury; neuroprotection; spreading depression
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  Data: <i>Date Created: </i>20260321 <i>Date Completed: </i>20260701 <i>Latest Revision: </i>20260915
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  Data: 10.1177/0271678X261417186
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        Value: 10.1177/0271678X261417186
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      – Code: eng
        Text: English
    PhysicalDescription:
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        StartPage: 1759
    Subjects:
      – SubjectFull: Neurons pathology
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Animals
        Type: general
      – SubjectFull: Brain Ischemia physiopathology
        Type: general
      – SubjectFull: Brain Ischemia pathology
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      – SubjectFull: Cell Death physiology
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      – SubjectFull: Cortical Spreading Depression physiology
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      – SubjectFull: Neuroprotection physiology
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      – TitleFull: Spreading depolarization: A wave that precedes and drives cerebral ischemic cell death-Target for neuroprotection.
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              Text: 2026 Jul
              Type: published
              Y: 2026
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            – TitleFull: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
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