Faculty Collaboration Database

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 2014 Feb;20(1):39-53

Date

01/15/2014

Pubmed ID

24420448

Pubmed Central ID

PMC3928514

DOI

10.1007/s13365-013-0227-1

Scopus ID

2-s2.0-84896698109 (requires institutional sign-in at Scopus site)   141 Citations

Abstract

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.

Author List

Akay C, Cooper M, Odeleye A, Jensen BK, White MG, Vassoler F, Gannon PJ, Mankowski J, Dorsey JL, Buch AM, Cross SA, Cook DR, Peña MM, Andersen ES, Christofidou-Solomidou M, Lindl KA, Zink MC, Clements J, Pierce RC, Kolson DL, Jordan-Sciutto KL

Author

Denise R. Cook-Snyder PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

AIDS Dementia Complex
Animals
Anti-Retroviral Agents
Blotting, Western
Brain
Cell Death
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Female
Fluorescent Antibody Technique
Macaca
Male
Neurons
Oxidative Stress
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species
Reverse Transcriptase Polymerase Chain Reaction