Metabolic Mechanisms of Injury and Neuroprotection with Riluzole against Hypoxic Damage in Mild Distraction Spinal Cord Injury
| dc.contributor.advisor | Romero-Ortega, Mario | |
| dc.creator | Shimizu, Eileen Nicole | |
| dc.date.accessioned | 2020-07-10T20:46:09Z | |
| dc.date.available | 2020-07-10T20:46:09Z | |
| dc.date.created | 2017-12 | |
| dc.date.issued | 2017-12 | |
| dc.date.submitted | December 2017 | |
| dc.date.updated | 2020-07-10T20:46:09Z | |
| dc.description.abstract | There are 100,000 spinal fusion surgeries each year in the United States to correct scoliotic spinal curvatures. Despite the use of electrophysiological monitoring during these procedures, there is an associated neurological complication rate as high as 17%, with complete paralysis as the most devastating complication. The surgery requires the application of multidirectional forces, which can include distraction, or stretching of the spinal column, ultimately compromising the vasculature of the spinal cord and creating an ischemic environment. The treatment of such spinal trauma is difficult in that it exists as a multiphase, multifactorial injury with an elaborate cascade of molecular and cellular changes. This secondary phase of injury can go undetected by electrophysiological monitoring and further exacerbate the damage. Despite the known occurrence of this secondary injury, the exact mechanisms following distraction injury remain elusive, making the development of neuroprotective strategies difficult. Therefore, in order characterize this injury, we previously developed an animal model of bidirectional spinal distraction to mimic the clinical scenario in which patients experience post-surgery functional deficits despite a lack of indication on electrophysiological monitoring during the surgery. Using this model, we demonstrated a hypoxic insult secondary to spine distraction which resulted in oxidative stress and an atraumatic injury but failed to determine the mechanism of injury. Furthermore, the development of a neuroprotective strategy was difficult, as a detailed examination of the specific secondary events elicited by spinal trauma is necessary to tailor treatment. Therefore, the body of work in this dissertation included mechanistically characterizing the secondary injury response in addition to evaluating a neuroprotective strategy in this injury paradigm. In Chapter 2, we leveraged our spinal distraction device to determine the cellular changes associated with distraction injury. Consistent with hypoxia and oxidative damage, we uncovered compromise to the vulnerable ventral motor neurons as indicated by cytoplasmic hypoplasia and nuclear pyknosis. In Chapter 3, we took a mechanistic approach to evaluate the molecular and genetic pathways affected by spinal distraction and subsequent neuroprotection with the sodium channel blocker, Riluzole. We suggest a possible failure to elicit a protective response to hypoxia and oxidative stress 24 hours after distraction injury, thereby indicating a potential area to target. We next utilized the sodium channel blocker, Riluzole, as a prophylactic neuroprotective and demonstrated its strong antioxidant properties which may promote cell survival. In Chapter 4, we systematically evaluated the neuroprotective effects of prophylactic administration of Riluzole in our animal model of distraction spinal cord injury. We demonstrated an alleviation of oxidative stress and metabolic impairment coupled with preserved gait associated with Riluzole treatment, thereby indicating it as a potent neuroprotectant in this clinical scenario. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | https://hdl.handle.net/10735.1/8705 | |
| dc.language.iso | en | |
| dc.rights | ©2017 Eileen Nicole Shimizu. All rights reserved. | |
| dc.subject | Spinal cord—Wounds and injuries | |
| dc.subject | Spinal cord—Surgery | |
| dc.subject | Neuroprotective agents | |
| dc.subject | Oxidative stress | |
| dc.subject | Sodium channels | |
| dc.title | Metabolic Mechanisms of Injury and Neuroprotection with Riluzole against Hypoxic Damage in Mild Distraction Spinal Cord Injury | |
| dc.type | Dissertation | |
| dc.type.material | text | |
| thesis.degree.department | Biomedical Engineering | |
| thesis.degree.grantor | The University of Texas at Dallas | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | PHD |
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