title: Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system.
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.
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy Bldg, Philadelphia, PA, 19104-6030, USA.
authors.forename: Cagla
authors.initials: C
authors.lastname: Akay
authors.forename: Michael
authors.initials: M
authors.lastname: Cooper
authors.forename: Akinleye
authors.initials: A
authors.lastname: Odeleye
authors.forename: Brigid K
authors.initials: BK
authors.lastname: Jensen
authors.forename: Michael G
authors.initials: MG
authors.lastname: White
authors.forename: Fair
authors.initials: F
authors.lastname: Vassoler
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Gannon
authors.forename: Joseph
authors.initials: J
authors.lastname: Mankowski
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Dorsey
authors.forename: Alison M
authors.initials: AM
authors.lastname: Buch
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Cross
authors.forename: Denise R
authors.initials: DR
authors.lastname: Cook
authors.forename: Michelle-Marie
authors.initials: MM
authors.lastname: Peña
authors.forename: Emily S
authors.initials: ES
authors.lastname: Andersen
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lindl
authors.forename: M Christine
authors.initials: MC
authors.lastname: Zink
authors.forename: Janice
authors.initials: J
authors.lastname: Clements
authors.forename: R Christopher
authors.initials: RC
authors.lastname: Pierce
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kolson
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology*; D000818:Animals; D044966:Anti-Retroviral Agents / Q000633:toxicity*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D008251:Macaca; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D044966:Anti-Retroviral Agents; D017382:Reactive Oxygen Species