Preclinical Animal Modeling to Investigate Redox-mediated Molecular Dysfunction in Traumatic Brain Injury

Authors

• Brandon Z. McDonald, University of Nebraska-LincolnFollow

First Advisor

Forrest M. Kievit

Date of this Version

5-2026

Document Type

Dissertation

Citation

A dissertation presented to the faculty of the Graduate College at the University of Nebraska in partial fulfillment of requirements for the degree of Doctor of Philosophy

Major: Biomedical Engineering

Under the supervision of Professor Forrest M. Kievit

Lincoln, Nebraska, May 2026

Comments

Copyright 2026, Brandon Z. McDonald. Used by permission

Abstract

Impacts associated with traumatic brain injury (TBI) induce a multitude of neurological morbidities mediated by a spread of biochemical dysfunction. Redox stress is a significant contributor to TBI pathophysiology and several redox stress markers have substantial evidence to support their role in diagnosing preclinical and clinical TBI. However, there is a critical need to verify their translational utility through correlations with behavioral, imaging, and molecular modalities. In chapter two, we examined the therapeutic efficacy of an antioxidant treatment (NPC3) using a controlled cortical impact (CCI) mouse model of TBI. NPC3 alleviated glial expression and reactivity while influencing the expression of several markers of redox-mediated metabolic dysfunction. Additionally, NPC3 moderated structural abnormalities, which positively correlated with a reduction in urinary 8-isoprostane concentration, demonstrating a relationship between redox stress and neurological deficits post-CCI. In chapter three, we examined the neurological deficits associated with craniectomy, the removal of a portion of the skull for gaining access to the dura, necessary for utilizing the CCI model. Craniectomy induced structural deficits and behavioral dysfunction, and these neurological deficits were further quantified by examining changes in neuroinflammation and blood brain barrier permeability. Lastly, in chapter 4, we examined the neurological deficits from a

repeated impact acceleration model of TBI and provided evidence for the utility of 8-isoprostane as a translational TBI biomarker. Repeated impacts induced time-course behavioral deficits which positively correlated with levels of urinary 8-isoprostane, indicating predictive power in delineating the neurological deficits observed in preclinical TBI. Additionally, urinary 8-isoprostane measurements strongly correlated with GFAP, a well-established canonical marker of TBI. Overall, these results suggest urinary 8-isoprostane is efficacious in predicting neurological dysfunction in a preclinical repeated TBI model. Future work should investigate 8-isoprostane in injury paradigms from different species to evaluate its conserved role in differentiating between heterogeneous TBI. Overall, this work provides evidence supporting the role of redox stress markers as sensitive, diagnostic biomarkers for assessing the broad disease heterogeneity associated with TBI and provide utility in assessing therapeutic strategies.

Advisor: Forrest M. Kievit