Autism spectrum disorder (ASD) is a lifelong disability that has seen a rise in prevalence from 1 in 150 children to 1 in 59 between 2000 and 2014. Patients show behavioral abnormalities in the areas of social interaction, communication, and restrictive and repetitive behaviors. As of now, the exact cause of ASD is unknown and literature points to multiple causes. The work contained within this dissertation explored the reduction of oxidative stress in brain tissue induced by xanthine oxidase (XO). Febuxostat is a new FDA approved XO-inhibitor that has been shown to be more selective and potent than allopurinol in patients with gout. The first study developed a computational model to calculate an effective diffusion constant (Deff) of lipophilic compounds, such as febuxostat, that can cross endothelial cells of the blood-brain barrier (BBB) by the transcellular pathway. In the second study, male juvenile autistic (BTBR) mice were treated with febuxostat for seven days followed by behavioral testing and quantification of oxidative stress in brain tissue compared to controls. Results of the first study showed that the lipophilic tracer chosen, as a substitute for febuxostat, could be modeled under the assumption of passive diffusion while experimental controls did not fit this model. The second study revealed no significant differences between BTBR mice that received febuxostat or the drug vehicle in both behavioral testing and quantification of oxidative stress in brain tissue. In the final study, of the four models proposed, one model was selected as the most plausible that considered transport into the CNS. As there is currently no literature surrounding tissue and organ ADME for febuxostat the final proposed model would need to be updated as new information becomes available. / PhD / Autism spectrum disorder (ASD) is a lifelong disability that has seen a rise in prevalence from 1 in 150 children to 1 in 59 between 2000 and 2014. Patients show behavioral abnormalities in the areas of (1) social interaction, how an individual acts and reacts to others around them, (2) communication, the use of and understanding of language and facial expressions, and (3) restrictive and repetitive behaviors where individuals may have focused interests on specific topics/subjects and stick to set routines. As of now, the exact cause of ASD is unknown and literature points to multiple causes. The work contained within this dissertation explored the reduction of oxidative stress in brain tissue induced by the enzyme xanthine oxidase (XO). Oxidative stress is noted as the imbalance between free radicals (pro-oxidant) and antioxidant defenses where the pro-oxidant levels are greater than the antioxidant defenses leading to cell and tissue damage. Febuxostat is a new FDA approved XO-inhibitor that has been shown to target and inhibit XO better than allopurinol (an older XO-inhibitor) in patients with gout. The first study developed a computational model to calculate an effective diffusion constant (Def f ) that explained the free movement of a compound (substance) across cells, also known as trancellular movement. The transcellular pathway is the direct movement of compounds into a cell that requires no additional cellular energy or specialized transport routes to get the compounds into the cell. In the second study, male juvenile autistic (BTBR) mice were treated with febuxostat for seven days followed by behavioral testing to study social interaction and restrictive and repetitive behaviors in autistic mice compared to non- autistic mice. Next, oxidative stress levels were measured in the brain tissue of autistic mice and compared to non-autistic mice. The third study developed four hypothesis-based human pharmacokinetic (PK) multi-compartment models of drug absorption, distribution, metabolism, and excretion (ADME). Pharmacokinetics is the study of what the body does to a drug once it is given, i.e how it gets into the bloodstream, where it goes in the body, how it is broken down, and how it is removed from the body . Compartments in PK models can be used to represent parts of the body such as blood, tissues, and organs. Results of the first study showed that the compound chosen as a substitute for febuxostat could be modeled under the assumption of passive diffusion, free movement across cells without use of energy or specialized routes, while the other compounds did not fit this model. The second study revealed no significant differences between autistic (BTBR) mice, those that received febuxostat treatment, and non-autistic mice for behavioral testing and oxidative stress levels in brain tissue. In the final study, of the four models proposed, one model was selected as the most plausible that considered drug movement into the brain and spinal cord regions. As there is currently no literature surrounding tissue and organ ADME for febuxostat the final proposed model would need to be updated as new information becomes available.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/87518 |
| Date | 06 February 2019 |
| Creators | Simmons, Jamelle Marquis |
| Contributors | Department of Biomedical Engineering and Mechanics, Lee, Yong Woo, Achenie, Luke E. K., Gabler, Hampton Clay, Rossmeisl, John H. Jr., Goldstein, Aaron S., Morozov, Alexei |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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