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* Division of Experimental Medicine and
Pulmonary Division, Beth Israel Deaconess Medical Center and Harvard Medical School, and
Center for Drug Discovery and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Research Grants HL80699 (to S.A.) and CA096805 (to H.K.A.) and the Blood Foundation (H.K.A.).
2 T.-S.L. and H.K.A. share first authorship.
3 Address correspondence and reprint requests to Dr. Shalom Avraham, Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 4 Blackfan Circle, Third Floor, Boston, MA 02115. E-mail address: savraham{at}bidmc.harvard.edu
4 Abbreviations used in this paper: BBB, blood-brain barrier; ACEA, arachidonyl-2'-chloroethylamide; 2-AG, 2-arachidonoylglycerol; AJ, adherens junction; BMEC, brain microvascular endothelial cell; EB, Evans blue; FAAH, fatty acid amide hydrolase; HAD, HIV-associated dementia; HBMEC, human BMEC; JAM, junctional adhesion molecule; SP, substance P; TEER, transendothelial electrical resistance; HC, 
9-tetrahydrocannabinol; TJ, tight junction; ZO, zonula occludens.
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