Date of Graduation
School of Medicine
Charles L Rosen
3.4 million concussions occur each year in the United States. Recent evidence suggests that some of these individuals are susceptible to neurodegenerative disease development following traumatic brain injury. The unknown factor is how acute injury contributes to this degenerative process. A prominent neurotrauma related neurodegenerative disease is chronic traumatic encephalopathy (CTE). CTE is defined by neurofibrillary tau tangles with a perivascular distribution and mood disturbances. In order to elucidate the pathologic changes associated with CTE, it is imperative to utilize adequate preclinical models. We have strategically developed and tested a clinically relevant rodent blast model. The model reliably produces a CTE phenotype including tauopathy, cell death, impulsivity, and cognitive decline. Using this validated model, we investigated several important secondary injury cascades that link acute brain injury to chronic neurodegenerative changes. More importantly, we pharmacologically targeted these pathways and found improved pathologic and behavioral outcomes. In chapter 1, we discuss the potential mechanisms linking acute injury to CTE in athletes and soldiers. In chapter 2, we highlight the physics behind the compression wave produced by our model and how this wave produces injury. In chapter 3, data is presented regarding the CTE phenotype generated by our model following repetitive blast exposure in rodents. Chapter 4 focuses on the role of blood brain barrier disruption and how targeting protein kinase C activity with bryostatin reduces this disruption. In chapter 5, we look at the role endoplasmic reticulum stress plays in human pathologic specimens from patients diagnosed with CTE and in rodents following repeat blast. We found that docosahexaenoic acid successfully targeted endoplasmic reticulum stress, reduced tauopathy, and improved cognitive performance. In chapter 6, we looked at lipoic acid and its role in reducing NADPH oxidative stress following repetitive neurotrauma. We found that lipoic acid reduces impulsive-like behavior and decreased cell death. Finally, in chapter 7 we discuss important strategies for improving preclinical models going forward and what needs to be investigated to improve our understanding of CTE. In this dissertation, we highlight important secondary injury cascades including blood brain barrier disruption, protein kinase C activity, endoplasmic reticulum stress, and oxidative stress that warrant further investigation for the development of novel treatment approaches for CTE.
Lucke-Wold, Brandon P., "Elucidating and Pharmacologically Targeting Secondary Injury Cascades following Neural Injury" (2016). Graduate Theses, Dissertations, and Problem Reports. 6120.