Abstract
HIV-1 infection has significant effect on the immune system as well as on the nervous system. Breakdown of the blood-brain barrier (BBB) is frequently observed in patients with HIV-associated dementia (HAD) despite lack of productive infection of human brain microvascular endothelial cells (HBMEC). Cellular products and viral proteins secreted by HIV-1 infected cells, such as the HIV-1 Gp120 envelope glycoprotein, play important roles in BBB impairment and HIV-associated dementia development. HBMEC are a major component of the BBB. Using cocultures of HBMEC and human astrocytes as a model system for human BBB as well as in vivo model, we show for the first time that cannabinoid agonists inhibited HIV-1 Gp120-induced calcium influx mediated by substance P and significantly decreased the permeability of HBMEC as well as prevented tight junction protein down-regulation of ZO-1, claudin-5, and JAM-1 in HBMEC. Furthermore, cannabinoid agonists inhibited the transmigration of human monocytes across the BBB and blocked the BBB permeability in vivo. These results demonstrate that cannabinoid agonists are able to restore the integrity of HBMEC and the BBB following insults by HIV-1 Gp120. These studies may lead to better strategies for treatment modalities targeted to the BBB following HIV-1 infection of the brain based on cannabinoid pharmacotherapies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AIDS Dementia Complex / enzymology
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AIDS Dementia Complex / pathology
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AIDS Dementia Complex / prevention & control
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AIDS Dementia Complex / virology
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Amidohydrolases / antagonists & inhibitors
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Anti-HIV Agents / pharmacology*
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Anti-HIV Agents / therapeutic use
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Arachidonic Acids / pharmacology*
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Arachidonic Acids / physiology
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Benzamides / pharmacology
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Benzamides / therapeutic use
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / physiology
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Brain / blood supply*
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Brain / drug effects
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Brain / pathology
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Brain / virology*
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Cannabinoid Receptor Modulators / agonists
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Cannabinoid Receptor Modulators / pharmacology*
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Cannabinoid Receptor Modulators / physiology
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Carbamates / pharmacology
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Carbamates / therapeutic use
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Cell Line
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Coculture Techniques
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Endocannabinoids
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology
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Endothelium, Vascular / physiology
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Endothelium, Vascular / virology*
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Glycerides / pharmacology*
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Glycerides / physiology
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HIV Envelope Protein gp120 / antagonists & inhibitors*
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HIV Envelope Protein gp120 / physiology
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HIV-1 / drug effects*
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HIV-1 / physiology
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Humans
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Microcirculation / drug effects
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Microcirculation / physiology
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Receptor, Cannabinoid, CB1 / physiology
Substances
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Anti-HIV Agents
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Arachidonic Acids
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Benzamides
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Cannabinoid Receptor Modulators
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Carbamates
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Endocannabinoids
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Glycerides
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HIV Envelope Protein gp120
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Receptor, Cannabinoid, CB1
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cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
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glyceryl 2-arachidonate
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Amidohydrolases
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fatty-acid amide hydrolase