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Abstract
Traumatic brain injury (TBI) represents a significant global health burden as it is a leading cause of death and disability worldwide. Children are particularly vulnerable to TBI insult and consequential deficits in learning, memory, behavior, and motor function that persist lifelong due to the disruption of ongoing developmental processes and neural maturation. Currently, there is no Food and Drug Administration (FDA) approved treatment option for TBI patients. Although the primary injury is unavoidable, the secondary injury cascade offers a therapeutic target in which neuroprotective and regenerative therapies may suppress or even reverse TBI damage and restore cognitive and motor function. Induced pluripotent stem cell-derived neural stem cells (iNSCs) have recently shown therapeutic promise through the secretion of neurotrophic factors and integration into the host neural circuitry that reduced lesion volumes, mitigated the inflammatory response, and augmented neurogenesis collectively supporting functional recovery. Moreover, current efforts to increase the therapeutic capacity of iNSCs suggests co-treatment with a structured treadmill walking exercise program may further ameliorate TBI pathophysiology and bolster significant neurological recovery through shared neuroprotective and regenerative pathways. Similarly, the alpha lipoic acid (ALA) chemical analog CMX-2043 may mitigate the secondary injury cascade due to its known anti-inflammatory and anti-apoptotic properties, capable of reducing neuroinflammation, preventing neural cell death, and mitigating tissue atrophy. Collectively, these neuroprotective and regenerative treatment strategies have demonstrated significant therapeutic efficacy within preclinical rodent models, however further investigation is required in a large animal model more representative of human TBI pathophysiology and functional outcomes. Therefore, the objectives of the studies within this dissertation were to evaluate the curative power of iNSC treatment, combined iNSCs and structured treadmill walking therapy, and CMX-2043 in a pediatric pig TBI model, and aid in the continued transition of these therapeutic options from the bench to the TBI patient bedside.