glyceryl-2-arachidonate and AIDS-Dementia-Complex

HIV-associated neurocognitive disorder (HAND) affects nearly half of all HIV-infected individuals. Synaptodendritic damage correlates with neurocognitive decline in HAND, and many studies have demonstrated that HIV-induced neuronal injury results from excitotoxic and inflammatory mechanisms. The endocannabinoid (eCB) system provides on-demand protection against excitotoxicity and neuroinflammation. Here, we discuss evidence of the neuroprotective and anti-inflammatory properties of the eCB system from in vitro and in vivo studies. We examine the pharmacology of the eCB system and evaluate the therapeutic potential of drugs that modulate eCB signaling to treat HAND. Finally, we provide perspective on the need for additional studies to clarify the role of the eCB system in HIV neurotoxicity and speculate that strategies that enhance eCB signaling might slow cognitive decline in HAND.

Topics: AIDS Dementia Complex; Amidohydrolases; Animals; Arachidonic Acids; Endocannabinoids; Glycerides; HIV Infections; HIV-1; Humans; Monoacylglycerol Lipases; Neurocognitive Disorders; Neurons; Polyunsaturated Alkamides; Receptors, Cannabinoid; Signal Transduction

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.

Topics: AIDS Dementia Complex; Amidohydrolases; Anti-HIV Agents; Arachidonic Acids; Benzamides; Blood-Brain Barrier; Brain; Cannabinoid Receptor Modulators; Carbamates; Cell Line; Coculture Techniques; Endocannabinoids; Endothelium, Vascular; Glycerides; HIV Envelope Protein gp120; HIV-1; Humans; Microcirculation; Receptor, Cannabinoid, CB1

The failure of the immune system to mount a successful attack on the human immunodeficiency virus (HIV) is an old enigma for AIDS research. The high mutational capacity of HIV, which unremittingly confuses the immune system, is a major factor in immune failure. But this alone cannot fully explain the certain and inescapable failure of the immune system, leading to full-blown AIDS. Here, we propose the hypothesis that endogenous cannabinoids, derived mostly from macrophages, might participate in the general failure of the immune system in HIV-infected individuals.

Topics: Acquired Immunodeficiency Syndrome; AIDS Dementia Complex; Animals; Arachidonic Acids; Cannabinoids; Endocannabinoids; Glycerides; HIV Envelope Protein gp120; HIV Envelope Protein gp160; HIV Infections; Humans; Immune Tolerance; Macrophages; Marijuana Smoking; Mice; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Signal Transduction