Recent work has implicated spreading depolarization (SD) as a key contributor the progression of acute brain injuries, however development of interventions selectively targeting SD has lagged behind. Initial clinical intervention efforts have focused on observations that relatively high doses of the sedative agent ketamine can completely suppress SD. However, blocking propagation of SD could theoretically prevent beneficial effects of SD in surrounding brain regions. Selective targeting of deleterious consequences of SD (rather than abolition) could be a useful adjunct approach, and be achieved with lower ketamine concentrations. We utilized a brain slice model to test whether deleterious consequences of SD could be prevented by ketamine, using concentrations that did not prevent the initiation and propagation of SD. Studies were conducted using murine brain slices, with focal KCl as an SD stimulus. Consequences of SD were assessed with electrophysiological and imaging measures of ionic and synaptic recovery. Under control conditions, ketamine (up to 30 μM) did not prevent SD, but significantly reduced neuronal Ca loading and the duration of associated extracellular potential shifts. Recovery of postsynaptic potentials after SD was also significantly accelerated. When SD was evoked on a background of mild metabolic compromise, neuronal recovery was substantially impaired. Under compromised conditions, the same concentrations of ketamine reduced ionic and metabolic loading during SD, sufficient to preserve functional recovery after repetitive SDs. These results suggest that lower concentrations of ketamine could be utilized to prevent damaging consequences of SD, while not blocking them outright and thereby preserving potentially protective effects of SD.
Spreading depolarizations (SDs) are profound disruptions of cellular homeostasis that slowly propagate through gray matter and present an extraordinary metabolic challenge to brain tissue. Recent work has shown that SDs occur commonly in human patients in the neurointensive care setting and have established a compelling case for their importance in the pathophysiology of acute brain injury. The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in September of 2018 included a discussion session focused on the question of "Which SDs are deleterious to brain tissue?" iCSD is attended by investigators studying various animal species including invertebrates, in vivo and in vitro preparations, diseases of acute brain injury and migraine, computational modeling, and clinical brain injury, among other topics. The discussion included general agreement on many key issues, but also revealed divergent views on some topics that are relevant to the design of clinical interventions targeting SDs. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was then formally collated, reviewed and incorporated into the final document. It is hoped that this report will stimulate collection of data that are needed to develop a more nuanced understanding of SD in different pathophysiological states, as the field continues to move toward effective clinical interventions.
KCB), daniela.pietrobon@unipd.it (DP) both basal glutamate and plume frequency predicted the onset of spreading depolarization in WT and FHM2 animals, providing a novel mechanism in migraine with aura and by extension the many other neurological disorders where spreading depolarizations occur.
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