Date of Award

2022

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

College of Natural Science and Mathematics, Biological Sciences

First Advisor

Daniel A. Linseman

Second Advisor

Scott A. Barbee

Third Advisor

Yan Qin

Fourth Advisor

Karen Krukowski

Fifth Advisor

Ann-Charlotte Granholm-Bentley

Keywords

Amyotrophic lateral sclerosis, Anti-inflammatory, Antioxidants, Biomarkers, Nutraceutical, Traumatic brain injury

Abstract

Mild traumatic brain injury (mTBI), yielding a Glascow Coma Scale of 13-15, is the most commonly occurring severity of TBI. Pathology from mTBI consists of blood brain barrier disruption, neuroinflammation, oxidative stress, excitotoxicity, mitochondrial dysfunction, protein aggregation, axonal degeneration, and resulting neuronal death. These processes deplete the body’s endogenous antioxidant system. We report a retrospective analysis of antioxidant blood biomarkers in patients with a history of mTBI from a local sports medicine clinic, Resilience Code. We found persistent sex-specific antioxidant depletions in mTBI patients associated with worsened symptomology.

Certain populations, such as athletes, are at high risk for repetitive mTBI (rmTBI). There are currently no FDA approved treatments for rmTBI for high-risk populations. We propose Immunocal®, a glutathione precursor supplement, as a preventative and restorative treatment for rmTBI. We show that Immunocal® significantly reduces astrogliosis at 2 weeks and 2 months in mice post-rmTBI and microgliosis at 72 hours following more severe repetitive mild-moderate TBI.

Persistent pathology from rmTBI has been linked to an increased risk for developing neurodegenerative disease like amyotrophic lateral sclerosis (ALS). This devastating disease is characterized by motor neuron death and a prognosis of 2-5 years following diagnosis. Pathology mirrors that of mTBI and consists of oxidative stress, neuroinflammation, mitochondrial dysfunction, excitotoxicity, protein aggregation, and changes to axonal transport and structure. We explored protocatechuic acid (PCA), a phenolic anthocyanin metabolite, as a treatment in the hSOD1G93A mouse model of ALS. PCA has been well studied for its antioxidant properties in other models of neurodegeneration. When administered at symptom onset, PCA prolonged survival, improved motor function, reduced gliosis, and offered significant neuroprotection in hSOD1G93A mice.

It is hypothesized that rmTBI results in an increased oxidative stress burden and subsequent antioxidant depletion. These persist when left untreated and may contribute to the development of neurodegenerative diseases like ALS. The connection between rmTBI and ALS should be further studied using preclinical models such as the hSOD1G93A mouse model of ALS. Treatment with nutraceutical therapeutics, such as glutathione precursors (Immunocal®) or anthocyanin metabolites (PCA), could restore antioxidant reserves and reduce rmTBI pathology, ultimately reducing the risk for developing neurodegenerative disease.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Lilia A. Koza

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

348 pgs

Discipline

Cellular biology, Molecular biology, Neurosciences

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