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Blood-brain barrier abnormalities caused by HIV-1 gp120: mechanistic and therapeutic implications.
ScientificWorldJournal. 2012; 2012:482575.S

Abstract

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.

Authors+Show Affiliations

Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street Room 255 Philadelphia, PA 19107, USA. jplouboutin@hotmail.comNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Review

Language

eng

PubMed ID

22448134

Citation

Louboutin, Jean-Pierre, and David S. Strayer. "Blood-brain Barrier Abnormalities Caused By HIV-1 Gp120: Mechanistic and Therapeutic Implications." TheScientificWorldJournal, vol. 2012, 2012, p. 482575.
Louboutin JP, Strayer DS. Blood-brain barrier abnormalities caused by HIV-1 gp120: mechanistic and therapeutic implications. ScientificWorldJournal. 2012;2012:482575.
Louboutin, J. P., & Strayer, D. S. (2012). Blood-brain barrier abnormalities caused by HIV-1 gp120: mechanistic and therapeutic implications. TheScientificWorldJournal, 2012, 482575. https://doi.org/10.1100/2012/482575
Louboutin JP, Strayer DS. Blood-brain Barrier Abnormalities Caused By HIV-1 Gp120: Mechanistic and Therapeutic Implications. ScientificWorldJournal. 2012;2012:482575. PubMed PMID: 22448134.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blood-brain barrier abnormalities caused by HIV-1 gp120: mechanistic and therapeutic implications. AU - Louboutin,Jean-Pierre, AU - Strayer,David S, Y1 - 2012/02/01/ PY - 2011/10/09/received PY - 2011/11/20/accepted PY - 2012/3/27/entrez PY - 2012/3/27/pubmed PY - 2012/7/14/medline SP - 482575 EP - 482575 JF - TheScientificWorldJournal JO - ScientificWorldJournal VL - 2012 N2 - 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. SN - 1537-744X UR - https://www.unboundmedicine.com/medline/citation/22448134/Blood_brain_barrier_abnormalities_caused_by_HIV_1_gp120:_mechanistic_and_therapeutic_implications_ L2 - https://doi.org/10.1100/2012/482575 DB - PRIME DP - Unbound Medicine ER -