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

Abstract

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.

Pathophysiology and Current Drug Treatments for Post-Stroke Depression: A Review

“…The cause of early brain injury can be best explained by glutamate excitotoxicity. As mentioned, when glutamate is released in excess, neuronal hyperexcitation results, thereby instigating post-stroke torrents that can lead to secondary neuronal damage [ 46 ]. On the other hand, the spreading depolarization (SD) theory asserts that the injury to neurons is sometimes evoked by metabolic stress rather than by excessive glutamate release.…”

“…The interference of the electrochemical membrane and neuronal swelling in the grey matter of the grain is primarily caused by the SD mechanism. The process causes various diseases and conditions, including concussion, intracerebral hemorrhage, ischemic stroke, and migraine-associated aura [ 46 ]. The brain is vulnerable to ischemic damage that can continue progressively for months.…”

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

“…Here, the state of constant depolarization leads to neuronal cell death, likely through calcium-dependent activation of BAX [115,127], among others. Constant depolarization for more than 15 minutes leads to neuronal cell death in the ischemic core, whereas SD in the penumbra occurs with a delay [127].…”

Modeling the heterogeneity of sodium and calcium homeostasis between cortical and hippocampal astrocytes and its impact on bioenergetics

“…Specifically, we aim to provide deeper insight into the role of NMDA and AMPA receptors in the observed heterogeneity in Na + and Ca 2+ homeostasis in astrocytes in the two brain regions and the downstream effects of this heterogeneity. In the later part of the paper, we focus on the effect of heterogenous expression levels of NMDA receptors on Na + and Ca 2+ dynamics and ATP consumption in the cortical and hippocampal astrocytes when stimulated by a high concentration of glutamate or NMDA with the activity of Na + /K + -ATPase suppressed as would be the case in numerous pathologies such as ischemic stroke, migraine, and traumatic brain injury (Hansen and Zeuthen, 1981 ; Dreier, 2011 ; Ayata and Lauritzen, 2015 ; Enger et al, 2015 ; Hu and Song, 2017 ; Murata et al, 2020 ; Andrew et al, 2022 ).…”