Journal Article

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

Pierce, R. Christopher, Akay, Cagla, Dorsey, Jamie L., Kolson, Dennis L., Lindl, Kathryn A., Peña, Michelle-Marie, Zink, M. Christine, White, Michael G., Cross, Stephanie A., Odeleye, Akinleye, Gannon, Patrick J., Vassoler, Fair, Andersen, Emily S., Mankowski, Joseph, Christofidou-Solomidou, Melpo, Clements, Janice, Cook, Denise R., Jensen, Brigid K., Buch, Alison M., Jordan-Sciutto, Kelly L., Cooper, Michael

2014

Overview

HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.

• Publisher: Springer US,Nature Publishing Group
• Subject: Acquired immune deficiency syndrome / AIDS / AIDS Dementia Complex - pathology / Animals / Anti-Retroviral Agents - toxicity / Antiretroviral agents / Antiviral agents / Atherosclerosis / Biomedical and Life Sciences / Biomedicine / Blotting, Western / Brain - drug effects / Brain - pathology / Brain - virology / Cell Death - drug effects / Cellular stress response / Central nervous system / Cognition / Disease Models, Animal / Drug dosages / Drug therapy / Enzyme-Linked Immunosorbent Assay / Experiments / Female / Fluorescent Antibody Technique / Fumaric acid / HIV / Human immunodeficiency virus / Immunology / Infectious Diseases / Lipid metabolism / Macaca / Macaca nemestrina / Male / Mitochondrial DNA / Nervous system / Neurology / Neurons - drug effects / Neurons - pathology / Neurosciences / Neurotoxicity / Oxidative metabolism / Oxidative stress / Oxidative Stress - drug effects / Pharmacokinetics / Polyclonal antibodies / Protein turnover / Rats / Rats, Sprague-Dawley / Reactive oxygen species / Reactive Oxygen Species - metabolism / Reagents / Reverse Transcriptase Polymerase Chain Reaction / Toxicity / Virology