Tag Archives: CB(1) and CB(2) receptors

Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis.

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“Cannabinoids from cannabis (Cannabis sativa) are anti-inflammatory and have inhibitory effects on the proliferation of a number of tumorigenic cell lines, some of which are mediated via cannabinoid receptors.

Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation.

Psoriasis is an inflammatory disease also characterised in part by epidermal keratinocyte hyper-proliferation.

OBJECTIVE:

We investigated the plant cannabinoids Delta-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol for their ability to inhibit the proliferation of a hyper-proliferating human keratinocyte cell line and for any involvement of cannabinoid receptors.

CONCLUSION:

The results indicate that while CB receptors may have a circumstantial role in keratinocyte proliferation, they do not contribute significantly to this process.

 Our results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.”

http://www.ncbi.nlm.nih.gov/pubmed/17157480

Cannabis and Δ9-tetrahydrocannabinol (THC) for weight loss?

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“Obesity is one of the highest preventable causes of morbidity and mortality in the developed world. It has been well known for a long time that exposure to cannabis produces an increase of appetite (a phenomenon referred to as the ‘munchies’). This phenomenon led to an exploration of the role of the endocannabinoid system in the regulation of obesity and associated metabolic syndrome.

This effort subsequently led to the development of a successful therapeutic approach for obesity that consisted of blocking the cannabinoid CB1 receptors using ligands such as Rimonabant in order to produce weight loss and improve metabolic profile. Despite being efficacious, Rimonabant was associated with increased rates of depression and anxiety and therefore removed from the market.

We recently discovered that the prevalence of obesity is paradoxically much lower in cannabis users as compared to non-users and that this difference is not accounted for by tobacco smoking status and is still present after adjusting for variables such as sex and age.

Here, we propose that this effect is directly related to exposure to the Δ(9)-tetrahydrocannabinol (THC) present in cannabis smoke.

We therefore propose the seemingly paradoxical hypothesis that THC or a THC/cannabidiol combination drug may produce weight loss and may be a useful therapeutic for the treatment of obesity and its complications.”

http://www.ncbi.nlm.nih.gov/pubmed/23410498

Cannabinoid receptor subtypes 1 and 2 mediate long-lasting neuroprotection and improve motor behavior deficits after transient focal cerebral ischemia.

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“The endocannabinoid system is crucially involved in the regulation of brain activity and inflammation… we show that the endocannabinoid system assembles a comprehensive machinery to defend the brain against the devastating consequences of cerebral ischemia.

 In summary, this study underlines the therapeutic potential of CB1 and/or CB2 receptor agonists against neurodegenerative diseases or injuries involving acute or chronic imbalances of cerebral blood flow and energy consumption.”

http://www.ncbi.nlm.nih.gov/pubmed/23069763

WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway.

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“Cannabinoids have been shown to exert neuroprotective effects in a plethora of neurodegenerative conditions.

Over the past decade, some studies demonstrate that cannabinoids can interact with nuclear peroxisome proliferator-activated receptors (PPARs).We investigated protective properties of WIN55212-2 (WIN, a non-selective cannabinoid receptor agonist) in beta-amyloid (Aβ)-induced neurodegeneration in rat hippocampus and possible involvement of PPAR-gamma (PPAR-γ). Aβ (1-42) was injected into the hippocampus of male rats. Animals were administered by intracerebroventricular rout the following treatments on days 1, 3, 5, 7: vehicle, WIN, GW9662 (selective PPAR-γ antagonist) plus WIN, AM251 (selective CB₁ receptor antagonist) plus WIN, SR144528 (selective CB₂ receptor antagonist) plus WIN, each of antagonists alone. Injection of Aβ-induced spatial memory impairment and a dramatic rise in hippocampal TNF-α, active caspase 3, nuclear NF-kB levels and TUNEL-positive neurons. WIN administration significantly improved memory function and diminished the elevated levels of these markers, while antagonizing either CB₁ or CB₂ receptor subtype partially attenuated the protective effects. Intriguingly, WIN significantly increased PPAR-γ level and transcriptional activity, the latter being partially inhibited with AM251 but not with SR144528. The enhancing effect on PPAR-γ pathway was crucial to WIN-induced neuroprotection since GW9662 partially reversed the beneficial actions of WIN. Co-administration of the three antagonists led to the complete abrogation of WIN effects.

Our findings indicate that WIN exerts neuroprotective and anti-inflammatory actions against Aβ damage through both CB₁ and CB₂ receptors. Of great note, both direct and CB₁-mediated increase in PPAR-γ signaling also contributes to WIN-induced neuroprotection.”

http://www.ncbi.nlm.nih.gov/pubmed/22634229

TEMPLE SCIENTISTS WEAKEN HIV INFECTION IN IMMUNE CELLS USING SYNTHETIC AGENTS RELATED TO ACTIVE INGREDIENT IN MARIJUANA

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“HIV, the virus that causes AIDS, is notorious for hiding within certain types of cells, where it reproduces at a slowed rate and eventually gives rise to chronic inflammation, despite drug therapy. But researchers at Temple University School of Medicine’s Department of Pathology and Laboratory Medicine and Center for Substance Abuse Research (CSAR) recently discovered that synthetic anti-inflammatory substances distantly related to the active ingredient of marijuana may be able to take the punch out of HIV while inside one of its major hideouts – immune cells known as macrophages. 

The breakthrough comes at a crucial time in the HIV/AIDS pandemic…

To better understand the connection between inflammation and neurocognitive conditions linked to long-term exposure to HIV, Ramirez and colleagues looked specifically at the CB2 receptor, a protein located on the surface of macrophages. CB2 is a binding site for substances called cannabinoids, the primary active compounds of cannabis (marijuana), and it may play a role in blocking inflammation in the CNS. Unlike its counterpart, the CB1 receptor, which is found primarily on neurons in the brain, CB2 does not mediate the psychoactive effects for which cannabis is popularly known.

Ramirez explained that there has been much pharmacological interest in developing agents that selectively target CB2. Ideally, these compounds would help limit chronic inflammatory responses and would not bind to CB1. The most promising compounds are those derived from THC (tetrahydrocannabinol), the main active substance in cannabis. 

The scientists landed on their discovery by conducting a series of experiments in a well-established, non-clinical HIV macrophage cell model. They began by treating the HIV-infected cells with one of three different synthetic CB2-activating compounds. The cells were then sampled periodically to measure the activity of an enzyme called reverse transcriptase, which is essential for HIV replication. After seven days, the team found that all three compounds had successfully attenuated HIV replication. The experiments and findings are detailed in the May issue of the Journal of Leukocyte Biology. 

The results suggest that selective CB2 agonists could potentially be used in tandem with existing antiretroviral drugs, opening the door to the generation of new drug therapies for HIV/AIDS. The data also support the idea that the human immune system could be leveraged to fight HIV infection. 

“Our study suggests that the body’s own natural defenses can be made more powerful to fight some of the worst symptoms of HIV,” Persidsky explained. He also noted that stimulating CB2 receptors in white blood cells could produce similar benefits against other viral infections.”

More: http://www.temple.edu/medicine/hiv_immune_cells.htm

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

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

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

Synthetic Agents Related To Active Ingredient In Marijuana Weaken HIV Infection – MedicalNewsToday

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“HIV, the virus that causes AIDS, is notorious for hiding within certain types of cells, where it reproduces at a slowed rate and eventually gives rise to chronic inflammation, despite drug therapy. But researchers at Temple University School of Medicine’s Department of Pathology and Laboratory Medicine and Center for Substance Abuse Research (CSAR) recently discovered that synthetic anti-inflammatory substances distantly related to the active ingredient of marijuana may be able to take the punch out of HIV while inside one of its major hideouts – immune cells known as macrophages.

The breakthrough comes at a crucial time in the HIV/AIDS pandemic…

To better understand the connection between inflammation and neurocognitive conditions linked to long-term exposure to HIV, Ramirez and colleagues looked specifically at the CB2 receptor, a protein located on the surface of macrophages. CB2 is a binding site for substances called cannabinoids, the primary active compounds of cannabis (marijuana), and it may play a role in blocking inflammation in the CNS. Unlike its counterpart, the CB1 receptor, which is found primarily on neurons in the brain, CB2 does not mediate the psychoactive effects for which cannabis is popularly known.

Ramirez explained that there has been much pharmacological interest in developing agents that selectively target CB2. Ideally, these compounds would help limit chronic inflammatory responses and would not bind to CB1.

The most promising compounds are those derived from THC (tetrahydrocannabinol), the main active substance in cannabis.”

More: http://www.medicalnewstoday.com/releases/259980.php

Synthetic derivatives of THC may weaken HIV-1 infection to enhance antiviral therapies – MedicalXpress

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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.

“The synthetic compounds we used in our study may show promise in helping the body fight HIV-1 infection,'” said Yuri Persidsky, M.D., Ph.D., a researcher involved in the work from the Department of Pathology and Laboratory Medicine at Temple University School of Medicine in Philadelphia, PA. “As compounds like these are improved further and made widely available, we will continue to explore their potential to fight other viral diseases that are notoriously difficult to treat.”

To make this discovery, scientists used a cell culture model to infect human macrophages with HIV-1 and added synthetic compounds similar to the active ingredient in marijuana to activate the CB2 receptor. At different times during the infection, samples from the culture were taken to see if the replication of the HIV virus was decreased. The researchers observed diminished HIV growth and a possible protective effect from some HIV-1 complications.

“HIV/AIDS has posed one of the most significant health challenges in modern medicine,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. “Recent high profile vaccine failures mean that all options need to be on the table to prevent or treat this devastating infection. Research on the role of cannabinoid type 2 receptors and viral infection may one day allow targeting these receptors to be part of combination therapies that use exploit multiple weaknesses of the virus simultaneously.””

http://medicalxpress.com/news/2013-04-synthetic-derivatives-thc-weaken-hiv-.html