Tag Archives: cannabinoid receptors

Cannabinoid Receptor 2 Protects against Acute Experimental Sepsis in Mice.

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“The systemic inflammatory response syndrome can be self-limited or can progress to severe sepsis and septic shock. Despite significant advances in the understanding of the molecular and cellular mechanisms of septic shock, it is still one of the most frequent and serious problems confronting clinicians in the treatments. And the effects of cannabinoid receptor 2 (CB2R) on the sepsis still remain undefined.

 The present study was aimed to explore the role and mechanism of CB2R in acute sepsis model of mice. Here, we found that mice were more vulnerable for lipopolysaccharide- (LPS-) induced death and inflammation after CB2R deletion (CB2R(-/-)). CB2R agonist, GW405833, could significantly extend the survival rate and decrease serum proinflammatory cytokines in LPS-treated mice. GW405833 dose-dependently inhibits proinflammatory cytokines release in splenocytes and peritoneal macrophages as well as splenocytes proliferation, and these effects were partly abolished in CB2R(-/-) splenocytes but completely abolished in CB2R(-/-) peritoneal macrophages. Further studies showed that GW405833 inhibits LPS-induced phosphorylation of ERK1/2 and STAT3 and blocks I κ B α degradation and NF- κ B p65 nuclear translocation in macrophages.

 All data together showed that CB2R provides a protection and is a potential therapeutic target for the sepsis.”

http://www.ncbi.nlm.nih.gov/pubmed/23781122

Expression, surface immobilization, and characterization of functional recombinant cannabinoid receptor CB2.

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Human peripheral cannabinoid receptor CB2, a G protein-coupled receptor (GPCR) involved in regulation of immune response has become an important target for pharmaceutical drug development.

 Structural and functional studies on CB2 may benefit from immobilization of the purified and functional receptor onto a suitable surface at a controlled density and, preferably in a uniform orientation. The goal of this project was to develop a generic strategy for preparation of functional recombinant CB2 and immobilization at solid interfaces. Expression of CB2 as a fusion with Rho-tag (peptide composed of the last nine amino acids of rhodopsin) in E. coli was evaluated in terms of protein levels, accessibility of the tag, and activity of the receptor. The structural integrity of CB2 was tested by ligand binding to the receptor solubilized in detergent micelles, captured on tag-specific monoclonal 1D4 antibody-coated resin. Highly pure and functional CB2 was obtained by sequential chromatography on a 1D4- and Ni-NTA- resin and its affinity to the 1D4 antibody characterized by surface plasmon resonance (SPR). Either the purified receptor or fusion CB2 from the crude cell extract was captured onto a 1D4 -coated CM4 chip (Biacore) in a quantitative fashion at uniform orientation as demonstrated by the SPR signal. Furthermore, the accessibility of the extracellular surface of immobilized CB2 and the affinity of interaction with a novel monoclonal antibody NAA-1 was studied by SPR.

 In summary, we present an integral strategy for purification, surface immobilization, ligand- and antibody binding studies of functional cannabinoid receptor CB2.”

http://www.ncbi.nlm.nih.gov/pubmed/23777860

Synthetic Compounds From Marijuana Appear to Fight HIV

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“Synthetic anti-inflammatory compounds derived from the active ingredient of marijuana appear to show potential as anti-HIV agents, Wired.co.uk reports. Publishing their findings in the Journal of Leukocyte Biology, researchers from Temple University School of Medicine’s Department of Pathology and Laboratory Medicine and Center for Substance Abuse Research (CSAR) studied synthetic derivations of THC, or tetrahydrocannabinol, a key chemical compound in marijuana, in cultures of HIV-infected cells.

Cannabinoids, which are the primary active compounds in marijuana, bind to proteins called CB2 receptors on the surface of macrophage immune cells. The CB2 site may play a role in reducing inflammation in the central nervous system, which is a major concern for people living with HIV, even those whose virus is fully suppressed thanks to antiretrovirals (ARVs). It is the CB1 receptors, mostly found in neurons in the brain, however, that cause marijuana’s psychoactive effects. So synthetic THC that has been developed to bind only to CB2 receptors should not make people stoned.

It is believed that macrophage cells, which are found throughout the body, are a major component of the HIV reservoir and are probably the first cells infected after sexual transmission of the virus.

Using a non-clinical cell model, the investigators treated HIV-infected macrophages with one of three different synthetic compounds that bind to CB2. By periodically measuring the activity of the enzyme reverse transcriptase, which HIV needs to replicate itself, the investigators concluded after a seven-day period that all three compounds fought HIV replication.

The findings suggest that these “CB2 agonists” could be a potential addition to ARV therapy, and also that the human immune system could be prompted to fight the virus using similar mechanisms.”

http://www.aidsmeds.com/articles/pot_CB2_1667_23905.shtml

Marijuana and its CD4 Receptors: A New HIV Treatment Strategy?

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“Drugs that target one of the two cellular receptors stimulated by the active ingredient in marijuana may prove to be effective at blocking a form of HIV that has been linked to faster disease progression during late stages of the infection.

Though the PLoS One research report highlighting these findings—published March 20 by a team of scientists at Mt. Sinai School of Medicine in New York—stops short of concluding that marijuana is one of nature’s best antiretrovirals, the authors suggest that further study of cannabinoids is needed to ultimately discover drugs with both antiviral and symptom-reducing properties.

Marijuana—purchased legally or illegally and either smoked or ingested—along with its synthetic counterpart Marinol (dronabinol) are used by many people living with HIV to manage various symptoms of illness, including pain, depression and weight loss.

The numerous effects of marijuana are the result of chemical interactions between the drug’s active ingredient, tetrahydrocannabinol (THC), and two receptors on a variety of cells in the body: cannabinoid receptor 1 (CR1) and cannabinoid receptor 2 (CR2)…

Using a cannabinoid receptor agonist—a THC-like compound—her team found that activation of CR2 inhibited CXCR4-tropic HIV infection. It did this, not by altering the number of CXCR4 receptors on CD4 cells—this is a therapeutic approach being explored by others—but rather by blocking the receptor’s “signaling process” and interaction with HIV. 

According to the PLoS One report, activation of CR2 blocked the ability of CXCR4-tropic virus to infect other cells by 30 to 60 percent. “This inhibition is pronounced in resting cells,” the researchers explain, “which are a target of CXCR4-tropic HIV.”

“Developing a drug that triggers only [CR2] as an adjunctive treatment to standard antiviral medication may help alleviate the symptoms of late-stage AIDS and prevent the virus from spreading,” said Dr. Costantino in an accompanying news announcement.”

More: http://www.aidsmeds.com/articles/hiv_marijuana_cannabinoids_1667_22119.shtml#.Ub8Pcix9Dhs.twitter

Turned-Off Cannabinoid Receptor Turns on Colorectal Tumor Growth – MDAnderson

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“Researchers find CB1 suppresses tumors, a new potential path for treatment, prevention.”

 “New preclinical research shows that cannabinoid cell surface receptor CB1 plays a tumor-suppressing role in human colorectal cancer, scientists report in the Aug. 1 edition of the journal Cancer Research.

CB1 is well-established for relieving pain and nausea, elevating mood and stimulating appetite by serving as a docking station for the cannabinoid group of signaling molecules. It now may serve as a new path for cancer prevention or treatment.

“Potential application of cannabinoids as anti-tumor drugs is an exciting prospect, because cannabinoid agonists are being evaluated now to treat the side-effects of chemotherapy and radiation therapy,” DuBois said.

 “Turning CB1 back on and then treating with a cannabinoid agonist could provide a new approach to colorectal cancer treatment or prevention.”

Cannabinoids are a group of ligands that serve a variety of cell-signaling roles. Some are produced by the body internally (endocannabinoids). External cannabinoids include manmade versions and those present in plants, most famously the active ingredient in marijuana (THC).”

More:  http://www.mdanderson.org/newsroom/news-releases/2008/turned-off-cannabinoid-receptor-turns-on-colorectal-tumor-growth.html

Turned-off Cannabinoid Receptor Turns On Colorectal Tumor Growth – CB1 Suppresses Tumors, A New Potential Path For Treatment, Prevention

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“New preclinical research shows that cannabinoid cell surface receptor CB1 plays a tumor-suppressing role in human colorectal cancer, scientists report in the Aug. 1 edition of the journal Cancer Research.

CB1 is well-established for relieving pain and nausea, elevating mood and stimulating appetite by serving as a docking station for the cannabinoid group of signaling molecules. It now may serve as a new path for cancer prevention or treatment.

“Potential application of cannabinoids as anti-tumor drugs is an exciting prospect, because cannabinoid agonists are being evaluated now to treat the side-effects of chemotherapy and radiation therapy,” DuBois said. “Turning CB1 back on and then treating with a cannabinoid agonist could provide a new approach to colorectal cancer treatment or prevention.”

Cannabinoids are a group of ligands that serve a variety of cell-signaling roles. Some are produced by the body internally (endocannabinoids). External cannabinoids include manmade versions and those present in plants, most famously the active ingredient in marijuana (THC).”

More: http://www.medicalnewstoday.com/releases/117055.php

Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells.

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“The anti-tumoral effects of cannabinoids have been described in different tumor systems, including pancreatic adenocarcinoma, but their mechanism of action remains unclear.

We used cannabinoids specific for the CB1 (ACPA) and CB2 (GW) receptors and metabolomic analyses to unravel the potential pathways mediating cannabinoid-dependent inhibition of pancreatic cancer cell growth. Panc1 cells treated with cannabinoids show elevated AMPK activation induced by a ROS-dependent increase of AMP/ATP ratio. ROS promote nuclear translocation of GAPDH, which is further amplified by AMPK, thereby attenuating glycolysis. Furthermore, ROS determine the accumulation of NADH, suggestive of a blockage in the respiratory chain, which in turn inhibits the Krebs cycle. Concomitantly, inhibition of Akt/c-Myc pathway leads to decreased activity of both the pyruvate kinase isoform M2 (PKM2), further downregulating glycolysis, and glutamine uptake.

Altogether, these alterations of pancreatic cancer cell metabolism mediated by cannabinoids result in a strong induction of autophagy and in the inhibition of cell growth.”

http://www.ncbi.nlm.nih.gov/pubmed/23764845

Compounds That Stimulate The Cannabinoid Type 2 Receptor In White Blood Cells Can Weaken HIV-1 Infection – MedicalNewsToday

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“A new use for compounds related in composition to the active ingredient in marijuana may be on the horizon: a new research report published in the Journal of Leukocyte Biology shows that compounds that stimulate the cannabinoid type 2 (CB2) receptor in white blood cells, specifically macrophages, appear to weaken HIV-1 infection. The CB2 receptor is the molecular link through which the pharmaceutical properties of cannabis are manifested. Diminishing HIV-1 infection in this manner might make current anti-viral therapies more effective and provide some protection against certain HIV-1 complications.”

More:  http://www.medicalnewstoday.com/releases/259885.php

Marijuana-Like Compounds Fight AIDS, Study Finds

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“Marijuana-like drugs can do more for AIDS patients than simply help them with their nausea or loss of appetite, according to a new study.

Doctor Tipster found new research published in the medical journal PLoS One that suggests marijuana-like compounds actually fight the HIV virus in late-stage AIDS patients.

Researchers told Doctor Tipster that they already know “cannabinoid drugs” like marijuana can have a therapeutic effect in AIDS patients. But they wanted to further understand how they “influence the spread of the virus itself.”

The study found that “cannabinoid receptors” are triggered by marijuana-like compounds and can actually block the spread of the HIV virus throughout the body.”

More: http://www.huffingtonpost.com/2012/03/22/marijuana-fights-aids_n_1373224.html

Human Immunodeficiency Virus In Late-Stage AIDS Inhibited By Marijuana-Like Chemicals – MedicalNewsToday

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“Mount Sinai School of Medicine researchers have discovered that marijuana-like chemicals trigger receptors on human immune cells that can directly inhibit a type of human immunodeficiency virus (HIV) found in late-stage AIDS, according to new findings published online in the journal PLoS ONE.

Medical marijuana is prescribed to treat pain, debilitating weight loss and appetite suppression, side effects that are common in advanced AIDS. This is the first study to reveal how the marijuana receptors found on immune cells – called cannabinoid receptors CB1 and CB2 – can influence the spread of the virus. Understanding the effect of these receptors on the virus could help scientists develop new drugs to slow the progression of AIDS.

“We knew that cannabinoid drugs like marijuana can have a therapeutic effect in AIDS patients, but did not understand how they influence the spread of the virus itself,” said study author Cristina Costantino, PhD, Postdoctoral Fellow in the Department of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine. “We wanted to explore cannabinoid receptors as a target for pharmaceutical interventions that treat the symptoms of late-stage AIDS and prevent further progression of the disease without the undesirable side effects of medical marijuana.”

HIV infects active immune cells that carry the viral receptor CD4, which makes these cells unable to fight off the infection. In order to spread, the virus requires that “resting” immune cells be activated. In advanced AIDS, HIV mutates so it can infect these resting cells, gaining entry into the cell by using a signaling receptor called CXCR4. By treating the cells with a cannabinoid agonist that triggers CB2, Dr. Costantino and the Mount Sinai team found that CB2 blocked the signaling process, and suppressed infection in resting immune cells.

Triggering CB1 causes the drug high associated with marijuana, making it undesirable for physicians to prescribe. The researchers wanted to explore therapies that would target CB2 only. The Mount Sinai team infected healthy immune cells with HIV, then treated them with a chemical that triggers CB2 called an agonist. They found that the drug reduced the infection of the remaining cells.

“Developing a drug that triggers only CB2 as an adjunctive treatment to standard antiviral medication may help alleviate the symptoms of late-stage AIDS and prevent the virus from spreading,” said Dr. Costantino. Because HIV does not use CXCR4 to enhance immune cell infection in the early stages of infection, CB2 agonists appear to be an effective antiviral drug only in late-stage disease.

As a result of this discovery, the research team led by Benjamin Chen, MD, PhD, Associate Professor of Infectious Diseases, and Lakshmi Devi, PhD, Professor of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine, plans to develop a mouse model of late-stage AIDS in order to test the efficacy of a drug that triggers CB2 in vivo. In 2009 Dr. Chen was part of a team that captured on video for the first time the transfer of HIV from infected T-cells to uninfected T-cells.”

http://www.medicalnewstoday.com/releases/243183.php