Alcohol/HIV-Induced Neurodeficit and Circumvention by Neuroprotective Agent
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Alcohol Use Disorder (AUD) remains a major problem in the United States, with usage varying between acute (binge) and chronic (heavy usage) staging. Alcohol Use Disorders affect 14.5 million people, with 9 million men and 5.5 million women. In the case of alcohol abuse, the effect of alcohol has been very well studied on the fetus but understanding of the chronic effect of alcohol abuse on neurotoxicity in the adult population, especially with comorbid conditions, such as Wernicke’s and Korsakoff’s Encephalopathy, remains more limited. Alcohol use and infection with the Human Immunodeficiency Virus-1 (HIV-1) in the United States is relatively common, with 30 to 60 % of these individuals having AUDs. These patients are exposed to different viral proteins that are known to be neurotoxic in the central nervous system. The combined effects of alcohol induced neurotoxicity with HIV-induced neurotoxicity are the interest of the current project. We have utilized the HIV-1 transactivator of transcription (Tat) protein as a model for HIV infection in an animal model. This is a widely accepted model that has been used to study aspects of HIV infection. Through use of this animal model, the work demonstrates that chronic exposure to alcohol and Tat creates a deficit in neurocognitive function with concomitant changes in receptors, cytokines and other inflammatory substances and molecules. This is important to keep in mind about changes in receptors and cytokines because the levels and changes can lead to the perpetuation of that neurodeficit. In this model, animals were treated with alcohol for 12 weeks. Tat is introduced by use of a transgenic animal line that has been treated the same way as control animals. The animals were subjected to a behavioral battery that tested different types of memory, anxiety, and motor function. We have found that treated animals exhibited additive, meaning the effects of the substances are combined, synergistic, meaning the substances work in concert to cause drug effect, or antagonistic, meaning the substances work against each other to cause no drug effects, which ultimately created an increased neurodeficit. Importantly, this work has also identified sex differences that are evident with treatment by HIV-1 Tat and alcohol, and these may be clinically relevant for treatment of patients with HIV-1 infection combined with alcohol abuse. Understanding sex difference or how drugs and other xenobiotics affect the individual is important because of development of different treatment strategies. This work evaluated the use of peroxisome proliferator activated receptor (PPAR) agonist on its ability to help alleviate the neurodeficit caused by Tat. The animals completed the described behavior battery above allowed us to identify the drug effects and potential changes in sex difference. In Chapter 1, we introduce the pharmacology and toxicology of alcohol, exposure plans and types of toxicity studies, HIV-1 Tat and HIV Associated Neurocognitive Disorders, and PPAR γ agonist pharmacology and toxicology. We also provide a detailed effort to link all of these topics together to further the study described below. In Chapter 2, we propose and carry out a two-pronged study to demonstrate prolonged exposure to alcohol in a controlled setting. We also examine synaptic protein analysis to ascertain the neurodeficit incurred from prolonged exposure to alcohol. In Chapter 3, we propose and carry out a three-pronged study to investigate prolonged exposure to alcohol, as well as to HIV-1 Tat. We also investigate how the resulting neurodeficit changes cytokine and receptors, and at how drug effect influences these changes. In Chapter 4, we propose and carry out a three-pronged study to demonstrate the neuroprotective properties of PPAR γ agonist, Rosiglitazone. We investigate the efficacy of this treatment using an animal study, and further investigate the effects on receptors and cytokines. We also evaluate the type of drug effect rosiglitazone exerts in the system. In Chapter 5, we conclude by giving an overview of our results. We also provide some commentary on the use of personalized, precision medicine approach to help with treatment of HIV-1 and alcohol abuse in populations. Further studies using animal models and three different clinical trial options for expand the goals of this work that are ultimately proposed.
Table of Contents
Introduction -- Long term alcohol use causes neurodeficit: an exposure plan and consequences -- Alcohol/HIV-1 Tat induced neurodeficit causes behavioral, receptor, and ligand changes -- PPAR y agonist helps ameliorate HIV-1 Tat induced neurodeficit -- Summation of research activities and future directions
Ph.D. (Doctor of Philosophy)