Cannabinoids Inhibit HIV-1 Gp120-Mediated Insults in Brain Microvascular Endothelial Cells

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.

Cannabinoid Inhibition of Macrophage Migration to the Trans-Activating (Tat) Protein of HIV-1 Is Linked to the CB2Cannabinoid Receptor

“…HIV-1 infection in this compartment is associated with progressive neurological impairments, including changes in cognitive and motor function and behavior (Lu et al, 2008). The degree of neurological impairment in HIV-associated dementia (HAD) and encephalitis does not correlate with viral load in the CNS but rather with the degree of monocyte infiltration and microglial activation (Glass et al, 1993).…”

“…Recent reports indicate that cannabinoids inhibit viral expression and downregulate CC chemokine receptor 5 (CCR5), a chemokine receptor that is a coreceptor for HIV-1 entry (Rock et al, 2007). In addition, cannabinoid receptor agonists have been reported to decrease significantly the permeability of human brain microvascular endothelial cells induced by Gp120 by preventing the down-regulation of integral tight junction proteins (Lu et al, 2008). Given the importance of macrophage infiltration into the CNS in the pathology of HIV infection and that cannabinoids have been shown to have anti-inflammatory properties (reviewed in Cabral and Staab, 2005) that include inhibition of macrophage migration (Raborn et al, 2008), the effect of cannabinoids on macrophage migration to the HIV-1 protein Tat was evaluated.…”

Endocannabinoids in cerebrovascular regulation

“…3), indicating the importance of this receptor in modulating neurotransmission (137). In the CNS, the expression of CB1 receptors was also demonstrated in astrocytes, microglial cells, pial vessels, cerebral microvascular smooth muscle cells, human brain endothelium, and pericytes (37,78,81,131,222,259) (Fig. 3).…”

“…Activated microglial cells from mice exhibit the highest CB2 receptor density on the leading edges (the front of migrating polarized cells), which may mediate their migration toward the source of endocannabinoid release, i.e., damaged neurons (247). Cerebrovascular endothelial cells express CB2 receptors together with CB1 and TRPV1 receptors, and these receptors are functional and possibly cooperative (81,131). Zhang et al (259) reported CB2 receptor expression in endothelial and smooth muscle cells of cerebral blood vessels, pericytes, astrocytes, and microglia.…”

Blood-Brain Barrier Disruption and Encephalitis in Animal Models of AIDS

“…More complex models involve monolayers of endothelial cells cultured above astrocytes, either on top of a collagen matrix (Biegel andPachter, 1994, Biegel et al, 1995) or on opposite sides of a membrane (Lu et al, 2008, Persidsky et al, 1997, Eugenin et al, 2006. The coculture allows tight junction formation to occur.…”