Spreading Depolarizations and Neuronal Vulnerability

University Of New Mexico Health Scis Ctr, Albuquerque NM

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY This project addresses mechanisms that underlie the progression of acute brain injuries, including stroke and trauma. Our long-term goal is to inform interventions that can be applied at delayed time points, and ultimately translated to clinical studies to improve survival and quality of life of survivors. Our project is focused on the phenomenon of spreading depolarization (SD). Recent clinical data have provided exciting evidence that clusters of SD waves cause progression of damage for many days in stroke and trauma patients. During the last funding period, we made progress in understanding how bursts of glutamate release during SD can lead to injury, and our work has led to initial clinical testing of pharmacologic approaches to block SD. However, these interventions still require sedation of patients, so alternative approaches are needed. In addition, the clinical situation is complex, since beneficial effects of SD could contribute to survival or recovery of peri-infarct tissues. An important challenge now is to understand whether and how SD may have beneficial effects, and whether the balance between detrimental and beneficial effects of SD can be shifted. This project uses brain slices and animal models to identify fundamental mechanisms that underlie beneficial effects of SD, and approaches to support compromised tissues to recover from repeated SD episodes. Our central hypothesis is that the balance between detrimental and beneficial effects of SD is determined by the metabolic competence of the brain tissue that it invades. We propose that bouts of SD produce both short and long-term adaptation in metabolically competent tissue. We will test whether these adaptations have significant consequences on brain recovery, and whether providing improved metabolic support or selective targeting of deleterious consequences of SD can significantly improve outcomes. Specific Aim 1 tests the hypothesis that SD activates short-term protective mechanisms, which take effect over seconds to minutes, and can be exploited to support neuronal survival during SD clusters. Studies in brain slices will examine protective diffusible factors generated by SD and by support with metabolic substrates. Specific Aim 2 tests the hypothesis that SD activates beneficial pathways that promote neuronal protection, recovery, and repair over hours to days. A focal stroke model will be used to: a) test whether invasion of SD into surviving peri-infarct tissues can promote survival, and b) identify pathways that inhibit neuronal death pathways and enhance mechanisms required for remodeling (over days to weeks). Specific Aim 3 tests the hypothesis that the balance between damaging and beneficial effects of SD can be shifted by modifying either the recovery from individual SD events or long-term adaptive processes. Successful completion of these aims will yield insights essential for future refinements and improved treatments for stroke and other acute brain injuries.