Biomedical Sciences ETDs

Publication Date

5-1-2013

Abstract

The expansion of the ischemic core into surrounding penumbral tissue has prompted researchers to finds ways to limit this progression in hopes of providing better outcomes for patients suffering from stroke. Current therapeutic strategies are limited, and new therapies that can be delivered at late time-points are needed. Zn2+ has been well documented to contribute to ischemic injury progression, and chelation of Zn2+ significantly improves neuronal survival, even when administered hours after the initial insult. However, determining the source of this Zn2+ and the toxic mechanisms involved in ischemia remain unclear. Over the past 10 years, clinical recordings have provided strong evidence that the occurrence of spreading depolarizations (SD) significantly contributes to the progression of numerous forms of brain injuries, including ischemic stroke. As these events occur repetitively for hours to days following the initial ischemic event, they pose as a prime candidate for the development of new therapeutic targets. These depolarizing events have the potential capability to release large amounts of synaptic Zn2+ into the extracellular space. The dissertation work presented here addresses whether synaptic Zn2+ release occurs during SD and if this source of Zn2+ is neurotoxic in the post-ischemic period. SD generated by either localized K+ applications or an in vitro model of ischemia (oxygen/glucose deprivation, OGD), resulted in large releases of synaptic Zn2+ in both hippocampal and neocortical tissues in vitro and led to postsynaptic accumulation. Zn2+ chelation was sufficient to delay the onset of OGD-SD, providing a mechanism for the beneficial effects of Zn2+ chelation seen previously. Additionally, elevating intracellular Zn2+ levels worsened the recovery after SD, likely through impaired metabolic function. Finally, synaptic Zn2+ release was detected following SD in vivo and this source of Zn2+ significantly contributed to ischemic injury. These results suggest that targeting synaptic Zn2+ stores or release during SD events could be a novel approach in treating ischemic brain injury. As SD events continue to occur days following the initial ischemic event, this suggests the ability to target these events at late time-points where current therapeutics are limited.

Keywords

Zinc, Spreading depression, ZnT3, Hippocampus, Neocortex

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Cunningham, Lee Anna

Second Committee Member

Valenzuela, C. Fernando

Third Committee Member

Pual, Surojit

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