Title

Highly Active Antiretroviral Therapy Drug Combination Induces Oxidative Stress and Mitochondrial Dysfunction in Immortalized Human Blood-brain Barrier Endothelial Cells

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 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 this condition. the viability of hCMEC/D3 cells (in vitro model of BBB) that were exposed to these drugs was significantly reduced after 72 h treatment, in a dose-dependent manner. Reactive oxygen species were highly elevated after the exposure, indicating that mechanisms that induce oxidative stress were involved. Measures of oxidative stress parameters, such as glutathione and malondialdehyde, were altered in the treated groups. Loss of mitochondrial membrane potential, as assessed by fluorescence microscopy and decreased levels of ATP, indicated that cytotoxicity 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. Pretreatment with the thiol antioxidant N-acetylcysteine amide reversed some of the pro-oxidant effects of AZT + IDV. Results from our in vitro studies indicate that the AZT + IDV combination may affect the BBB in HIV-infected individuals treated with HAART drugs.

Department(s)

Chemistry

Sponsor(s)

National Institute of Health (U.S.)
United States. Veterans Administration. Merit Review Boards

Library of Congress Subject Headings

Oxidative stress

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2011 Elsevier, All rights reserved.


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