Tag Archives: CB2

Therapeutic Utility of Cannabinoid Receptor Type 2 (CB2) Selective Agonists.

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“The cannabinoid receptor type 2 (CB2), is a class A GPCR that was cloned in 1993 while looking for an alternate receptor that could explain the pharmacological properties of 9- tetrahydrocannabinol. CB2 was identified among cDNAs based on its similarity in amino-acid sequence to the CB1 receptor and helped provide an explanation for the established effects of cannabinoids on the immune system.

In addition to the immune system, CB2 has widespread tissue expression and has been found in brain, PNS and GI tract. Several “mixed” cannabinoid agonists are currently in clinical use primarily for controlling pain and it is believed that selective CB2 agonism may afford a superior analgesic agent devoid of the centrally mediated CB1 effects.

Thus, selective CB2 receptor agonists represent high value putative therapeutics for treating pain and other disease states. In this perspective, we seek to provide a concise update of progress in the field.”

http://www.ncbi.nlm.nih.gov/pubmed/23865723

Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol.

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“This study examines the role of the cannabinoid CB2 receptor (CB2 r) on the vulnerability to ethanol consumption… These results suggest that deletion of the CB2 r gene increased preference for and vulnerability to ethanol consumption…

Future studies will determine the role of CB2 r as a target for the treatment of problems related with alcohol consumption.”

http://www.ncbi.nlm.nih.gov/pubmed/23855434

Anti-inflammatory compound from cannabis found in herbs

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“A compound found in cannabis as well as in herbs such as basil and oregano could help to treat inflammatory bowel diseases and arthritis, Swiss scientists believe.”

Model of the interaction of BCP with the CB2 receptor

“(E)-beta-caryophyllene (BCP) is an aromatic sesquiterpene that has used for many years as a food additive because of its peppery flavour. The researchers now say that it interacts selectively with one of two cannabinoid receptors, CB2, blocking the chemical signals that lead to inflammation without triggering cannabis’s mood-altering effects.
 
Many cannabinoids bind to the CB2 receptor, but few target it selectively. Most also interact with CB1, which is responsible for cannabis’ psychoactive properties. CB1 is found in brain tissue, whereas CB2is found only in cells elsewhere in the body.”
 

More:http://www.rsc.org/chemistryworld/News/2008/June/24060801.asp

Anti-inflammatory property of the cannabinoid receptor-2-selective agonist JWH-133 in a rodent model of autoimmune uveoretinitis.

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“Previous studies have shown that cannabinoids have anti-inflammatory and immune-modulating effects, but the precise mechanisms of action remain to be elucidated.

In this study, we investigated the effect of JWH 133, a selective agonist for cannabinoid receptor 2, the main receptor expressed on immune cells, in a model of autoimmune disease, experimental autoimmune uveoretinitis (EAU).

JWH 133 suppressed EAU in a dose-dependent manner (0.015-15 mg/kg), and the suppressive effect could be achieved in the disease-induction stage and the effector stage. Leukocytes from mice, which had been treated with JWH 133, had diminished responses to retinal peptide and mitogen Con A stimulation in vitro. In vivo JWH 133 treatment also abrogated leukocyte cytokine/chemokine production. Further in vitro studies indicated that JWH 133 down-regulated the TLR4 via Myd88 signal transduction, which may be responsible for its moderate, suppressive effect on antigen presentation. In vivo JWH 133 treatment (1 mg/kg) also suppressed leukocyte trafficking (rolling and infiltration) in inflamed retina as a result of an effect on reducing adhesion molecules CD162 (P-selectin glycoprotein ligand 1) and CD11a (LFA-1) expression on T cells.

In conclusion, the cannabinoid agonist JWH 133 has a high in vivo, anti-inflammatory property and may exert its effect via inhibiting the activation and function of autoreactive T cells and preventing leukocyte trafficking into the inflamed tissue.”

Full text: http://www.jleukbio.org/content/82/3/532.long

The role of CB1 in immune modulation by cannabinoids.

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“There is clear evidence that CB(2), historically referred to as the peripheral cannabinoid receptor, mediates many of the immune modulatory effects of cannabinoids.

 However, cannabinoid receptors cannot be classified simply as central or peripheral since CB(2) has been shown to play a role in the central nervous system (CNS) and CB(1) mediates many immune system effects. Although Cnr1 mRNA and CB(1) protein expression is lower than Cnr2 mRNA or CB(2) protein expression in cells of the immune system, several studies have shown direct modulation of immune function via CB(1) by endogenous and exogenous cannabinoids in T cells, innate cells, and to a lesser extent, B cells.

In addition, indirect, but CB(1)-dependent, mechanisms of immune modulation exist. In fact, the mechanism by which cannabinoids attenuate neuroinflammation via CB(1) is likely a combination of immune suppression and neuroprotection.

 Although many studies demonstrate that agonists for CB(1) are immune suppressive and anti-inflammatory, CB(1) antagonists also exhibit anti-inflammatory properties. Overall, the data demonstrate that many of the immune modulatory effects of cannabinoids are mediated via CB(1).”

http://www.ncbi.nlm.nih.gov/pubmed/23261520

Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions.

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“Previous studies have shown that modulation of the receptor-mediated cannabinoid system during neuroinflammation can produce potent neuroprotective and anti-inflammatory effects

…Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325902/

Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation.

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“There is now a large body of data indicating that the cannabinoid receptor type 2 (CB2) is linked to a variety of immune events. This functional relevance appears to be most salient in the course of inflammation, a process during which there is an increased number of receptors that are available for activation. Studies aimed at elucidating signal transduction events resulting from CB2 interaction with its native ligands, and of the role of exogenous cannabinoids in modulating this process, are providing novel insights into the role of CB2 in maintaining a homeostatic immune balance within the host. Furthermore, these studies suggest that the CB2 may serve as a selective molecular target for therapeutic manipulation of untoward immune responses, including those associated with a variety of neuropathies that exhibit a hyperinflammatory component.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768535/

Researchers Have Discovered Synthetic Agents Used To Treat HIV Inflammation – Medical News Today

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“HIV can cause serious inflammation, regardless of drug therapy, as it develops slowly in immune cells called macrophages. However, new research conducted at the Temple University School of Medicine’s Department of Pathology and Laboratory Medicine and Center for Substance Abuse Research (CSAR) has just found that there are synthetic agents with anti-inflammatory properties, related to the active ingredient in cannabis, THC (tetrahydrocannabinol) which could limit and treat the chronic inflammation.

These findings suggest that CB2 agonists could be used along with antiretroviral drugs which could lead to a new form of therapy for HIV/AIDS.

It also suggests that the human immune system itself could be used to fight off the HIV infection.

According to Persidsky: “Our study suggests that the body’s own natural defenses can be made more powerful to fight some of the worst symptoms of HIV.”

Stimulating CB2 receptors could also be applied for treating other infections.”

More: http://www.medicalnewstoday.com/articles/260152.php

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