DOI
https://doi.org/10.25772/CTZK-R359
Defense Date
2018
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
MaryPeace McRae, Pharm.D., Ph.D.
Abstract
According to UNAIDS 2016, over 37 million people worldwide were infected with human immunodeficiency virus (HIV) in 2016, with over 1.2 million people living with HIV in the United States. Of those, approximately one half will suffer from HIV-associated neurocognitive disorders (HAND), which is a spectrum of neurocognitive disorders ranging from asymptomatic neurocognitive impairment, to mild neurocognitive disorder, to HIV-associated dementia. While combination antiretroviral therapy (cART) has decreased the incidence of the most severe forms of HAND in patients with HIV, milder forms of HAND still persist. These defects can include decreased motor skills, cognitive abilities, memory, and attention. While patients with HIV are living longer thanks to cART, there are few to no long-term options for managing the neurocognitive defects caused by the chronic disease of HAND. Additionally, opiate abuse can increase both the incidence and severity of HAND. HAND may result due to poor antiretroviral drug (ARV) penetration across the blood-brain barrier (BBB). Thus, a better understanding of the effects of HIV and opiates on the BBB may result in improved therapies for HAND.
The Tat transgenic model was used to evaluate the effects of the HIV-1 viral protein Tat and morphine on blood-brain barrier leakiness using varied-sized paracellular compounds. Secondly, antiretroviral drug accumulation in the brain of Tat transgenic mice under Tat and/or morphine co-exposure was measured. Specifically, the single tablet regimen of Triumeq® (abacavir/lamivudine/dolutegravir) was studied in these mice and antiretroviral drug measured in both striatum and hippocampus brain regions and plasma via LC-MS/MS. Additionally, morphine and its metabolites were also measured via LC-MS/MS. Lastly, macrophage turnover within the caudate/putamen and phagocytic macrophage/microglia accumulation in the brain was measured in Tat transgenic mice under Tat and/or morphine conditions. Perivascular and parenchymal spaces were distinguished within the caudate/putamen, while overall phagocytic activity was measured in all other brain regions, including the nucleus accumbens, anterior cingulate cortex, primary motor cortex, somatosensory cortex, agranular insular cortex, and piriform cortex.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-11-2018