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

Andrew, R. David; Hartings, Jed A.; Ayata, Cenk; Brennan, K. C.; Dawson‐Scully, Ken; Farkas, Eszter; Herreras, Óscar; Kirov, Sergei A.; Müller, Michael; Ollen-Bittle, Nikita; Reiffurth, Clemens; Revah, Omer; Robertson, R. Meldrum; Shuttleworth, C. William; Ullah, Ghanim; Dreier, Jens P.

doi:10.1007/s12028-021-01431-w

Cited by 43 publications

(63 citation statements)

References 225 publications

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“…It is well-established that in response to transient hypoxic insult, synaptic transmission is interrupted, but neurons maintain their membrane potential, and reoxygenation restores synaptic transmission (Somjen, 2004). However, the occurrence of SD during hypoxia, as routinely observed in slices held at a gas-liquid interface, hastens rapid, irreversible neuronal injury (Müller and Somjen, 1999; Andrew et al, 2022). In contrast, SD cannot be triggered by hypoxia alone in slices submerged under normal ACSF superfusion (Croning and Haddad, 1998).…”

Section: Resultsmentioning

confidence: 99%

Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling

Álvarez-Merz

Fomitcheva

Sword

et al. 2022

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Bleeding into cerebral parenchyma during hemorrhagic stroke or head trauma leads to ischemia and release of plasmatic content, including amino acids (AA). Although excitotoxic AA have been extensively studied, little is known about non-excitatory AA during hypoxic injury. Hypoxia-induced synaptic depression becomes irreversible after adding non-excitatory AA to hippocampal slices, alongside their intracellular accumulation and increased tissue electrical resistance. A combination of four non-excitatory AA (L-alanine, glycine, L-glutamine, L-serine: AGQS) at plasmatic concentrations was applied to brain slices from transgenic mice expressing EGFP in pyramidal neurons or astrocytes during normoxia or hypoxia. Two-photon imaging, changes in light transmittance (LT), and electrophysiological field recordings followed by electron microscopy in hippocampal CA1 st. radiatum were used to monitor synaptic function concurrently with cellular swelling and injury. During normoxia, AGQS-induced increase in LT was due to astroglial but not neuronal swelling. Fast LT raise during hypoxia and AGQS manifested neuronal and astroglial swelling accompanied by a permanent loss of synaptic transmission and irreversible dendritic beading, signifying acute tissue damage. Neuronal injury was not triggered by spreading depolarization which did not occur in our experiments. Hypoxia without AGQS did not cause cell swelling, leaving dendrites intact. Inhibition of NMDA receptors prevented neuronal damage and irreversible loss of synaptic function. Deleterious effects of AGQS during hypoxia were prevented by alanine-serine-cysteine transporters (ASCT2) and volume-regulated anion channels (VRAC) blockers. Our findings suggest that swelling induced by intracellular accumulation of non-excitatory AA and release of excitotoxins through antiporters and VRAC may exacerbate the hypoxia-induced neuronal injury.Significance StatementLittle is known if non-excitatory amino acids (AA) contribute to cellular injury when released during bleeding, as in hemorrhagic stroke and head trauma. Alanine, glycine, glutamine, and serine are one of the most abundant in plasma. Remarkably, during hypoxia, these non-excitatory AA caused severe neuronal and astroglial swelling and irreversible dendritic injury alongside a permanent loss of synaptic function. Activation of NMDA receptors was implicated in the onset of damage. Experimental evidence pointed to the involvement of alanine-serine-cysteine transporter 2 (ASCT2) and volume-regulated anion channels (VRAC) as molecular mechanisms underlying AA-induced damage during hypoxia. A detailed understanding of how brain injury evolves with non-excitatory AA during hypoxia will help design brain recovery treatments in neurological conditions involving bleeding.

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Section: Resultsmentioning

confidence: 99%

Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling

Álvarez-Merz

Fomitcheva

Sword

et al. 2022

Preprint

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“…In contrast, the role of spreading depolarization (SD) in evoking acute brain damage is more compelling despite SD being underestimated or ignored for years by most researchers of brain ischemia. In this review, we briefly outline the importance of SD in early brain injury, with evidence presented in more detail in the accompanying reviews published in the current issue of Neurocritical Care [ 1 ]. We then address the glutamate excitotoxicity theory and compare it with the SD theory in terms of interpreting acute brain injury.…”

Section: Introductionmentioning

confidence: 99%

“…SD can be evoked by various noxious electrical, chemical, thermal, or mechanical disturbances of gray matter that stress the Na + /K + pump. Thus, SD is associated with a range of diseases and conditions, including migraine-associated aura, concussion, traumatic brain injury (TBI), subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, circulatory arrest, and brain death prior to circulatory collapse [ 1 , 9 – 14 ]. SD can also invade gray matter that has not been metabolically compromised, inducing a loss of neuronal activity termed “spreading depression” [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Background Within 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 Methods Literature pertaining to excitotoxicity and to SD over the past 60 years is critiqued. Results Excitotoxicity 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. Conclusions Spreading depolarizations better account for the acute neuronal injury arising from brain ischemia than does the early and excessive release of glutamate.

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“…Kearns et al investigate the links between microglial activation and SDs [12]. Finally, a set of perspectives explore our assumptions regarding the links between SDs and excitotoxicity and identify areas of contention in SD research that should inform future studies [13,14].…”

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confidence: 99%

Introduction to Spreading Depolarizations Special Edition Volume 2

Balu

Foreman

2022

Neurocrit Care

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

Cited by 43 publications

References 225 publications

Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling

Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling

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

Introduction to Spreading Depolarizations Special Edition Volume 2

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