anandamide and HIV-Infections

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

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

We demonstrate that immediate exposure to gp120 (5 min; 0.1 microg/ml) results in a significant shift of the macrophage population to an amoeboid and motile category (P<0.01; 91.7+/-5.5 vs. a control value of 42.4+/-4.2) and prior exposure with anti-gp120 antagonizes this shift. Acute exposure of the macrophages to morphine (10(-6) M) or anandamide (10(-6) M) resulted in the cells rounding up (shape factors of 0.84 and 0.87 respectively) and becoming non-motile. The action is blocked by prior treatment with the specific antagonists naloxone and SR 141716A. Chronic exposure (6 h) of the cells to all three agents resulted in a random migration pattern. Further, all agents blocked chemotaxis induced by DAMA and IL-1. Observation of the cells behavior during chronic exposure revealed a sporadic activity pattern with gp120 whereas morphine and anandamide first induced a period of inactivity which is followed by a period of activity (chemokinesis). Recent work from our laboratory has demonstrated that both morphine and anandamide acutely stimulate constitutive macrophage nitric oxide (NO) release, which then induces macrophage rounding and inactivity. It was therefore of interest to examine their behavior by exposing macrophages to the NO-donor SNAP. In a concentration dependent manner SNAP exhibited the same behavioral actions as both substances of abuse. Given this, we next determined if macrophages exposed to gp120 would release NO. We demonstrated that NO was released only when exposed to morphine and anandamide not gp120. Thus. the chemokinetic inducing activities of these agents may be the basis for excitotoxin liberation in neural tissues and/or a higher viral load in various organ systems since cellular adherence and random migration are stimulated.

Topics: Analysis of Variance; Arachidonic Acids; Cannabinoids; Cell Movement; Chemotaxis; Disease Susceptibility; Endocannabinoids; Enkephalin, Methionine; HIV Envelope Protein gp120; HIV Infections; Humans; In Vitro Techniques; Interleukin-1; Macrophages; Morphine; Narcotics; Nitric Oxide; Penicillamine; Polyunsaturated Alkamides