Date of Award

2010

Document Type

Campus Access Dissertation

Department

Biomedical Science

First Advisor

Rosemarie M. Booze

Abstract

HIV can induce marked and debilitating neurologic complications in infected children, often in spite of the use of Highly Active Antiretroviral Therapy. Clinical observations suggest a specific vulnerability of dopaminergic neurons, yet few studies have examined the possibility that these functional impairments may be associated with dopamine-specific pathology in pediatric patients. We utilized an in vivo model to 1) examine dopaminergic molecular alterations attributable to the effects of HIV infection in the CNS, 2) to determine if oxidative stress may contribute to the development of molecular dopaminergic alterations, and 3) to assess whether a neuroprotective attempt specific to oxidative stress associated with catecholaminergic activity may be mounted by the CNS. Periadolescent HIV-1 transgenic rats were confronted with a dopamine challenge, following which mesencephalic tissues were assayed to determine changes in the expression of biomarkers vital to dopamine neurotransmission. In assaying inherent differences between control and transgenic animals we observed a decrease in mRNA expression but no change in protein expression, suggesting a decrease in protein turnover. Following the dopamine challenge we observed a slight decrease in protein expression specific to dopamine-challenged transgenic animals with no change in mRNA, suggesting a minor gene-based compensatory mechanism that may attempt to rectify the decrease in protein expression. Assays of markers of oxidative stress-related damage indicate all treatment groups can to a similar degree prevent free radical-induced damage. Finally, we observed an overall decrease in gene expression related to an inherent antioxidant that was common amongst all transgenic animals, with no change in protein expression, confirming the lack of evidence for oxidative stress. Previous findings have demonstrated clear alterations in biomarkers for dopaminergic neurotransmission in a developmental model utilizing younger animals. These current findings, obtained in a developmental model that corresponds to the periadolescent period of human development, suggest an age-related shift in the vulnerability of midbrain dopamine systems to the neurotoxic effects of HIV.

Rights

© 2010, Katy Webb

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