Biomedical Sciences ETDs

Publication Date

Spring 4-14-2025

Abstract

Spreading depolarizations (SDs) are massive, slowly propagating waves that cause near-complete neuroglial depolarization and are energetically demanding for the brain. Past studies have established SDs as key contributors to secondary injury in tissue that lacks the metabolic supply to meet the energetic burden of repolarization after SD. Efforts to identify the mechanisms that cause deleterious consequences following SD have been ongoing, with significant results showing that blocking excitotoxic levels of Ca2+ from entering neurons through NMDA receptors prevents detrimental outcomes. While these studies have advanced the field, other mechanisms may also contribute to the metabolic burden of SD. This dissertation explored the potential alternative pathways that could contribute to SD-mediated injury in vulnerable brain. We identify a role of synaptic Zn2+ accumulation in delaying neuronal recovery from SD and prolonging the period of tissue vulnerability in metabolically depleted brain slices. Pharmacological interventions improved tissue outcomes either through chelation with a fast-acting Zn2+ chelator or by blockade of its entry through L-type voltage-dependent Ca2+ channels. Additionally, we examined how the experimental initiation site of SD in an in vivo model of stroke affects the expansion of ischemic injury. These data present 1) a clinically relevant mechanism that can be used to target SD-mediated injury in congruence with current interventions and 2) provide evidence that preclinical examination of SDs must be sure to accurately model the spontaneous occurrence of these events in clinical cases.

Keywords

spreading depression, zinc, L-type calcium channels, stroke, ischemia

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

C. Fernando Valenzuela

Second Committee Member

C. William Shuttleworth

Third Committee Member

Thomas C. Resta

Fourth Committee Member

Lee Anna Cunningham

Fifth Committee Member

Russell A. Morton

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