Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications

The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic...

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Main Authors: Jean-Pierre Louboutin, David S. Strayer
Format: Article
Language:English
Published: Wiley 2012-01-01
Series:The Scientific World Journal
Online Access:http://dx.doi.org/10.1100/2012/482575
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author Jean-Pierre Louboutin
David S. Strayer
author_facet Jean-Pierre Louboutin
David S. Strayer
author_sort Jean-Pierre Louboutin
collection DOAJ
description The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.
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spelling doaj-art-99a10bfd4afd4437921c78db82c083f32025-02-03T05:51:30ZengWileyThe Scientific World Journal1537-744X2012-01-01201210.1100/2012/482575482575Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic ImplicationsJean-Pierre Louboutin0David S. Strayer1Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street Room 255 Philadelphia, PA 19107, USADepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street Room 255 Philadelphia, PA 19107, USAThe blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.http://dx.doi.org/10.1100/2012/482575
spellingShingle Jean-Pierre Louboutin
David S. Strayer
Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications
The Scientific World Journal
title Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications
title_full Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications
title_fullStr Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications
title_full_unstemmed Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications
title_short Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications
title_sort blood brain barrier abnormalities caused by hiv 1 gp120 mechanistic and therapeutic implications
url http://dx.doi.org/10.1100/2012/482575
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