Doctoral Dissertations

Abstract

"The era of highly active antiretroviral therapy (HAART) has controlled AIDS and its related disorders considerably; however, the prevalence of HIV-1-associated neurocognitive disorders (HAND) has been on the rise in the post-HAART era. In view of these developments, we investigated whether a HAART drug combination of 3'-Azido-2', 3'-deoxythymidine (AZT) and Indinavir (IDV) can alter the functionality of the blood-brain barrier (BBB) endothelial cells, thereby exacerbating the condition. Viability of hCMEC/D3 cells (in vitro model of BBB) that were exposed to the drugs was significantly reduced after a 72 hr treatment, in a dose-dependent manner. Reactive oxygen species (ROS) were highly elevated after the exposure, indicating that mechanisms that induce oxidative stress were involved. Measures of oxidative stress such as glutathione (GSH) and malondialdehyde (MDA) were found to be altered in the treated groups. Loss of mitochondrial membrane potential (Δψm) assessed with fluorescent microscopy and decreased levels of ATP indicated that cytoxicity was mediated through mitochondrial dysfunction. Furthermore, AZT + IDV treatment caused apoptosis in endothelial cells as assessed by the expression of cytochrome c and procaspase-3 proteins. In vivo experiments with HIV-1 transgenic animal treated with AZT+ IDV showed decrease in GSH in the BBB and brain and increase in MDA levels in the BBB. Thiol antioxidant N-acetylcysteine amide (NACA) reversed some of the pro-oxidant effects of AZT+IDV in both invitro and invivo studies. Results from our studies indicate that the AZT + IDV combination can affect the BBB and may play a role in contributing to neurocognitive disorders in HIV-1 infected individuals treated with HAART drugs"--Abstract, page iii.

Advisor(s)

Ercal, Nuran

Committee Member(s)

Shannon, Katie
Whitefield, Philip D.
Mormile, Melanie R.
Sinn, Ekkehard

Department(s)

Chemistry

Degree Name

Ph. D. in Chemistry

Sponsor(s)

National Institutes of Health (U.S.)

Publisher

Missouri University of Science and Technology

Publication Date

Fall 2010

Pagination

x, 103 pages

Note about bibliography

Includes bibliographical references (pages 90-102).

Rights

© 2010 Kalyan Chakravarthy Reddy Manda, All rights reserved.

Document Type

Dissertation - Open Access

File Type

text

Language

English

Subject Headings

AZT (Drug)
Blood-brain barrier
Cognition disorders
Glutathione
Highly active antiretroviral therapy
Oxidative stress

Thesis Number

T 9702

Print OCLC #

746081985

Electronic OCLC #

694371023

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