Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment

Persistent Link:
http://hdl.handle.net/10150/610193
Title:
Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment
Author:
Dallas, Shannon; Block, Michelle; Thompson, Deborah; Bonini, Marcelo; Ronaldson, Patrick; Bendayan, Reina; Miller, David
Affiliation:
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA; Drug Metabolism and Pharmacokinetics, Drug Safety Sciences, Janssen R&D, LLC, Spring House, PA, USA; Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, VA, USA; Science and Technology Development, North Carolina Biotechnology Center, Research Triangle Park, NC, USA; Section of Cardiology and Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada; Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
Issue Date:
2013
Publisher:
BioMed Central
Citation:
Dallas et al. Journal of Neuroinflammation 2013, 10:58 http://www.jneuroinflammation.com/content/10/1/58
Journal:
Journal of Neuroinflammation
Rights:
© 2013 Dallas et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND:Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide.METHODS:To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent microglia exposed to the prototypical inflammatory mediator lipopolysaccharide (LPS).RESULTS:3H]-Saquinavir accumulation by microglia was rapid, and was increased up to two-fold in the presence of the specific P-glycoprotein inhibitor, PSC833. After six or 24 hours of exposure to 10 ng/ml LPS, saquinavir accumulation was decreased by up to 45%. LPS did not directly inhibit saquinavir transport, and did not affect P-glycoprotein protein expression. LPS exposure did not alter RNA and/or protein expression of other transporters including multidrug resistance-associated protein 1 and several solute carrier uptake transporters.CONCLUSIONS:The decrease in saquinavir accumulation in microglia following treatment with LPS is likely multi-factorial, since drug accumulation was attenuated by inhibitors of NF-kappabeta and the MEK1/2 pathway in the microglia cell line HAPI, and in primary microglia cultures from toll-like receptor 4 deficient mice. These data provide new pharmacological insights into why microglia act as a difficult-to-treat viral sanctuary site.
EISSN:
1742-2094
DOI:
10.1186/1742-2094-10-58
Keywords:
Drug transporters; HIV; Inflammation; MEK1/2; Microglia; Multidrug resistance proteins; NF-kappa β; P-glycoprotein; Saquinavir; Solute carrier uptake transporters; Toll-like receptor
Version:
Final published version
Additional Links:
http://www.jneuroinflammation.com/content/10/1/58

Full metadata record

DC FieldValue Language
dc.contributor.authorDallas, Shannonen
dc.contributor.authorBlock, Michelleen
dc.contributor.authorThompson, Deborahen
dc.contributor.authorBonini, Marceloen
dc.contributor.authorRonaldson, Patricken
dc.contributor.authorBendayan, Reinaen
dc.contributor.authorMiller, Daviden
dc.date.accessioned2016-05-20T09:00:43Z-
dc.date.available2016-05-20T09:00:43Z-
dc.date.issued2013en
dc.identifier.citationDallas et al. Journal of Neuroinflammation 2013, 10:58 http://www.jneuroinflammation.com/content/10/1/58en
dc.identifier.doi10.1186/1742-2094-10-58en
dc.identifier.urihttp://hdl.handle.net/10150/610193-
dc.description.abstractBACKGROUND:Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide.METHODS:To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent microglia exposed to the prototypical inflammatory mediator lipopolysaccharide (LPS).RESULTS:3H]-Saquinavir accumulation by microglia was rapid, and was increased up to two-fold in the presence of the specific P-glycoprotein inhibitor, PSC833. After six or 24 hours of exposure to 10 ng/ml LPS, saquinavir accumulation was decreased by up to 45%. LPS did not directly inhibit saquinavir transport, and did not affect P-glycoprotein protein expression. LPS exposure did not alter RNA and/or protein expression of other transporters including multidrug resistance-associated protein 1 and several solute carrier uptake transporters.CONCLUSIONS:The decrease in saquinavir accumulation in microglia following treatment with LPS is likely multi-factorial, since drug accumulation was attenuated by inhibitors of NF-kappabeta and the MEK1/2 pathway in the microglia cell line HAPI, and in primary microglia cultures from toll-like receptor 4 deficient mice. These data provide new pharmacological insights into why microglia act as a difficult-to-treat viral sanctuary site.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.jneuroinflammation.com/content/10/1/58en
dc.rights© 2013 Dallas et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.subjectDrug transportersen
dc.subjectHIVen
dc.subjectInflammationen
dc.subjectMEK1/2en
dc.subjectMicrogliaen
dc.subjectMultidrug resistance proteinsen
dc.subjectNF-kappa βen
dc.subjectP-glycoproteinen
dc.subjectSaquinaviren
dc.subjectSolute carrier uptake transportersen
dc.subjectToll-like receptoren
dc.titleMicroglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatmenten
dc.typeArticleen
dc.identifier.eissn1742-2094en
dc.contributor.departmentNational Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USAen
dc.contributor.departmentDrug Metabolism and Pharmacokinetics, Drug Safety Sciences, Janssen R&D, LLC, Spring House, PA, USAen
dc.contributor.departmentDepartment of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, VA, USAen
dc.contributor.departmentScience and Technology Development, North Carolina Biotechnology Center, Research Triangle Park, NC, USAen
dc.contributor.departmentSection of Cardiology and Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USAen
dc.contributor.departmentDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON, Canadaen
dc.contributor.departmentDepartment of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USAen
dc.identifier.journalJournal of Neuroinflammationen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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