High doses of ketamine to improve neuronal edema in subarachnoid hemorrhage: we should consider other undesirable organ targets

Honoré, Patrick M.; Mugisha, Aude; Kugener, Luc; Redant, Sébastien; Attou, Rachid; Gallerani, Andrea; Bels, David De

doi:10.1186/s13054-020-03004-3

Cited by 2 publications

(1 citation statement)

References 10 publications

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“…For example, ketamine is not only an NMDAR inhibitor but also inhibits norepinephrine and serotonin uptake, which could damage, for example, the kidneys. Yet in the clinical study [ 105 ], there was no evidence of acute kidney injury [ 107 ]. This could be because patients with brain injury are usually treated with high doses of catecholamines and that ketamine reduces the required dose because it inhibits norepinephrine uptake [ 108 ].…”

Section: Glutamate Release and Sdmentioning

confidence: 99%

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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Section: Glutamate Release and Sdmentioning

confidence: 99%

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

et al. 2022

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Ketamine-induced prevention of SD-associated late infarct progression in experimental ischemia

Zdunczyk,

Schumm,

Helgers

et al. 2024

Sci Rep

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Spreading depolarizations (SDs) occur frequently in patients with malignant hemispheric stroke. In animal-based experiments, SDs have been shown to cause secondary neuronal damage and infarct expansion during the initial period of infarct progression. In contrast, the influence of SDs during the delayed period is not well characterized yet. Here, we analyzed the impact of SDs in the delayed phase after cerebral ischemia and the potential protective effect of ketamine. Focal ischemia was induced by distal occlusion of the left middle cerebral artery in C57BL6/J mice. 24 h after occlusion, SDs were measured using electrocorticography and laser-speckle imaging in three different study groups: control group without SD induction, SD induction with potassium chloride, and SD induction with potassium chloride and ketamine administration. Infarct progression was evaluated by sequential MRI scans. 24 h after occlusion, we observed spontaneous SDs with a rate of 0.33 SDs/hour which increased during potassium chloride application (3.37 SDs/hour). The analysis of the neurovascular coupling revealed prolonged hypoemic and hyperemic responses in this group. Stroke volume increased even 24 h after stroke onset in the SD-group. Ketamine treatment caused a lesser pronounced hypoemic response and prevented infarct growth in the delayed phase after experimental ischemia. Induction of SDs with potassium chloride was significantly associated with stroke progression even 24 h after stroke onset. Therefore, SD might be a significant contributor to delayed stroke progression. Ketamine might be a possible drug to prevent SD-induced delayed stroke progression.

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High doses of ketamine to improve neuronal edema in subarachnoid hemorrhage: we should consider other undesirable organ targets

Cited by 2 publications

References 10 publications

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

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

Ketamine-induced prevention of SD-associated late infarct progression in experimental ischemia

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