Cargando…
Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system
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 toxic...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928514/ https://www.ncbi.nlm.nih.gov/pubmed/24420448 http://dx.doi.org/10.1007/s13365-013-0227-1 |
_version_ | 1782304276997996544 |
---|---|
author | Akay, Cagla Cooper, Michael Odeleye, Akinleye Jensen, Brigid K. White, Michael G. Vassoler, Fair Gannon, Patrick J. Mankowski, Joseph Dorsey, Jamie L. Buch, Alison M. Cross, Stephanie A. Cook, Denise R. Peña, Michelle-Marie Andersen, Emily S. Christofidou-Solomidou, Melpo Lindl, Kathryn A. Zink, M. Christine Clements, Janice Pierce, R. Christopher Kolson, Dennis L. Jordan-Sciutto, Kelly L. |
author_facet | Akay, Cagla Cooper, Michael Odeleye, Akinleye Jensen, Brigid K. White, Michael G. Vassoler, Fair Gannon, Patrick J. Mankowski, Joseph Dorsey, Jamie L. Buch, Alison M. Cross, Stephanie A. Cook, Denise R. Peña, Michelle-Marie Andersen, Emily S. Christofidou-Solomidou, Melpo Lindl, Kathryn A. Zink, M. Christine Clements, Janice Pierce, R. Christopher Kolson, Dennis L. Jordan-Sciutto, Kelly L. |
author_sort | Akay, Cagla |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3928514 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-39285142014-02-25 Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system Akay, Cagla Cooper, Michael Odeleye, Akinleye Jensen, Brigid K. White, Michael G. Vassoler, Fair Gannon, Patrick J. Mankowski, Joseph Dorsey, Jamie L. Buch, Alison M. Cross, Stephanie A. Cook, Denise R. Peña, Michelle-Marie Andersen, Emily S. Christofidou-Solomidou, Melpo Lindl, Kathryn A. Zink, M. Christine Clements, Janice Pierce, R. Christopher Kolson, Dennis L. Jordan-Sciutto, Kelly L. J Neurovirol Article 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. Springer US 2014-01-14 2014 /pmc/articles/PMC3928514/ /pubmed/24420448 http://dx.doi.org/10.1007/s13365-013-0227-1 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/2.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Article Akay, Cagla Cooper, Michael Odeleye, Akinleye Jensen, Brigid K. White, Michael G. Vassoler, Fair Gannon, Patrick J. Mankowski, Joseph Dorsey, Jamie L. Buch, Alison M. Cross, Stephanie A. Cook, Denise R. Peña, Michelle-Marie Andersen, Emily S. Christofidou-Solomidou, Melpo Lindl, Kathryn A. Zink, M. Christine Clements, Janice Pierce, R. Christopher Kolson, Dennis L. Jordan-Sciutto, Kelly L. Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system |
title | Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system |
title_full | Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system |
title_fullStr | Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system |
title_full_unstemmed | Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system |
title_short | Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system |
title_sort | antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928514/ https://www.ncbi.nlm.nih.gov/pubmed/24420448 http://dx.doi.org/10.1007/s13365-013-0227-1 |
work_keys_str_mv | AT akaycagla antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT coopermichael antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT odeleyeakinleye antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT jensenbrigidk antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT whitemichaelg antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT vassolerfair antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT gannonpatrickj antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT mankowskijoseph antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT dorseyjamiel antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT buchalisonm antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT crossstephaniea antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT cookdeniser antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT penamichellemarie antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT andersenemilys antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT christofidousolomidoumelpo antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT lindlkathryna antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT zinkmchristine antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT clementsjanice antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT piercerchristopher antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT kolsondennisl antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem AT jordansciuttokellyl antiretroviraldrugsinduceoxidativestressandneuronaldamageinthecentralnervoussystem |