Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Narendra Banik

Second Advisor

DeAnna L. Adkins

Third Advisor

Chris Gregory

Fourth Advisor

James Krause

Fifth Advisor

Abhay Varma

Abstract

Spinal cord injury affects more than 12,000 individuals in the US annually. Currently, no FDA approved drug treatment is available for the acute care of these individuals. Estrogen (E2), as a naturally occurring steroid hormone, is a potential answer. As a highly pleiotropic agent, E2 is known to have anti-inflammatory, anti-apoptotic, angiogenic, and neurotrophic properties, making it ideal for use in the treatment of a highly complex, multi-faceted condition such as SCI. Safety concerns around the use of high doses of E2 have limited its application clinically. To address these concerns, a nanoparticle delivery approach was used. Low doses of E2 (25 - 2.5 μg) were formulated in nanoparticles and embedded into gel patches that were placed directly on contused spinal cord tissue, allowing for focal delivery. Plasma E2 levels revealed exposure profiles distinct from traditional dose routes, potentially conferring increased efficacy. To further understand novel early, intermediate, and chronic neuroprotective mechanisms that E2 exerts, a 6hr, 48hr, and 28 day rat model of SCI was utilized. In the peracute (6hr) model, cytokine and chemokine profiling was conducted in plasma, tissue, and CSF which allowed for identification of biomarkers as well as novel targets of E2 regulation. Data revealed a panel of factors regulated by E2, including IL-6, MCP-1, and GRO-KC, etc. The intermediate model was used to test the hypothesis that E2 may drive neuroprotection through modulation of glial cell response. Data suggest E2 decreases various markers of glial cell reactivity and inflammation. Finally, a chronic model was used to assess the potential of a single low dose nanoparticle delivered E2 to drive improvements in locomotor function. The lowest single dose at which functional improvements may be seen, was found to be 5.0 μg of E2. These findings illustrate the ability of focally delivered nanoparticle formulated E2 to reduce plasma exposures to physiologically relevant levels while maintaining efficacy in a functional model. Taken together, these findings may help advance E2 into clinical evaluation at safer doses, thus providing a treatment options for SCI individuals.

Rights

All rights reserved. Copyright is held by the author.

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