Spreading depolarizations pose critical energy challenges in acute brain injury

Spreading depolarization (SD) is an electrochemical wave of neuronal depolarization mediated by extracellular K⁺ and glutamate, interacting with voltage-gated and ligand-gated ion channels. SD is increasingly recognized as a major cause of injury progression in stroke and brain trauma, where the mechanisms of SD-induced neuronal injury are intimately linked to energetic status and metabolic impairment. Here, I review the established working model of SD initiation and propagation. Then, I summarize the historical and recent evidence for the metabolic impact of SD, transitioning from a descriptive to a mechanistic working model of metabolic signaling and its potential to promote neuronal survival and resilience. I quantify the energetic cost of restoring ionic gradients eroded during SD, and the extent to which ion pumping impacts high-energy phosphate pools and the energy charge of affected tissue. I link energy deficits to adaptive increases in the utilization of glucose and O₂, and the resulting accumulation of lactic acid and CO₂ downstream of catabolic metabolic activity. Finally, I discuss the neuromodulatory and vasoactive paracrine signaling mediated by adenosine and acidosis, highlighting these metabolites' potential to protect vulnerable tissue in the context of high-frequency SD clusters.