Tag Archives: CB2

Betacaryophyllene – A phytocannabinoid as potential therapeutic modality for human sepsis?

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“Sepsis is a clinical condition resulting from a dysregulated immune response to an infection that leads to organ dysfunction. Despite numerous efforts to optimize treatment, sepsis remains to be the main cause of death in most intensive care units.

The endogenous cannabinoid system (ECS) plays an important role in inflammation. Cannabinoid receptor 2 (CB2R) activation is immunosuppressive, which might be beneficial during the hyper-inflammatory phase of sepsis.

Beta-caryophyllene (BCP) is a non-psychoactive natural cannabinoid (phytocannabinoid) found in Cannabis sativa and in essential oils of spices and food plants, that acts as a selective agonist of CB2R.

We propose BCP administration as novel treatment to reduce hyper-inflammation in human sepsis.”

https://www.ncbi.nlm.nih.gov/pubmed/29317072
http://www.medical-hypotheses.com/article/S0306-9877(17)30861-7/fulltext

Prospects for the Use of Cannabinoid Receptor Ligands for the Treatment of Metabolic Syndrome and Atherosclerosis: Analysis of Experimental and Clinical Data.

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“An antagonist of central cannabinoid CB1 receptors rimonabant causes weight loss in patients with obesity and metabolic syndrome, improves blood lipid parameters, increases the adiponectin level, decreases the rate of glucose and glycosylated hemoglobin in patients with diabetes mellitus type-2. However, rimonabant adverse effects include depression, anxiety, nausea, and dizziness which are apparently due to the blockade of central CB1 receptors.

In mice with a high-calorie diet, we defined that the blockade of peripheral CB1 receptors prevents obesity, steatosis of the liver, improves lipid and carbohydrate metabolism. Experimental studies suggest that peripheral CB2 receptor agonists have antiatherogenic effect. To validate the expediency of clinical research of CB2 receptor agonists in patients with atherosclerosis the comparative analysis of antiatherogenic properties of cannabinoids should be performed. In addition, experiments are needed on the combination use of cannabinoids with well-known antiatherogenic agents, such as statins.”

https://www.ncbi.nlm.nih.gov/pubmed/29308855

Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts.

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“Approximately 65 million adults in the US have periodontitis, causing tooth loss and decreased quality of life.

 Cannabinoids modulate immune responses, and endocannabinoids are prevalent during oral cavity inflammation. Targets for intervention in periodontal inflammation are cannabinoid type 1 and 2 receptors (CB1R, CB2R), particularly CB2R because its levels increase during inflammation.

We previously demonstrated that SMM-189 (CB2R inverse agonist) decreased pro-inflammatory cytokine production in primary microglial cells. The hypothesis of this study was that cannabinoids anandamide (AEA), HU-308 (CB2R selective agonist), and SMM-189 decrease pro-inflammatory IL-6 and MCP-1 production by primary human periodontal ligament fibroblasts (hPDLFs) stimulated with P. gingivalis LPS, TNF-α, or IL-1β.

CONCLUSION:

The effective inhibition of LPS, TNF-α, IL-1β stimulated IL-6 and MCP-1 production by CB2R ligands in hPDLFs suggests that targeting the endocannabinoid system may lead to development of novel drugs for periodontal therapy, aiding strategies to improve oral health.”

https://www.ncbi.nlm.nih.gov/pubmed/29274621

Activation of cannabinoid receptor type 2 by JWH133 alleviates bleomycin-induced pulmonary fibrosis in mice.

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“Activation of cannabinoid receptor type 2 has been shown to have anti-fibrosis function in skin and heart.

In this research, we aimed to investigate the role of cannabinoid receptor type 2 in pulmonary fibrosis in vitro and in vivo.

Our research indicated that activating cannabinoid receptor type 2 by a pharmacological method might be a potential strategy for pulmonary fibrosis.”  https://www.ncbi.nlm.nih.gov/pubmed/29262578

“In conclusion, we demonstrate that activating cannabinoid receptor type 2 by selective agonist JWH133 is a potential strategy for pulmonary fibrosis. Our researches offer a new choice for this life-threatening disease.” http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=21975&path[]=69664

Restoration of osteogenic differentiation by overexpression of cannabinoid receptor 2 in bone marrow mesenchymal stem cells isolated from osteoporotic patients.

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“Cannabinoid receptor 2 (CNR2) has a critical role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). CNR2 expression was found to be downregulated in osteoporotic patients.

The present study aimed to investigate the functionality of CNR2 in restoring osteogenic differentiation and mineralization of BMSCs isolated from osteoporotic patients.

The results demonstrated that overexpression of CNR2 in osteoporotic BMSCs increased ALP activity, promoted expression of osteogenic genes and enhanced deposition of mineralized extracellular matrix. In addition, phosphorylation of p38 MAPK was found to be increased by overexpression of CNR2.

In conclusion, the present study indicated that restoration of CNR2 recovered the osteogenic differentiation of BMSCs isolated from osteoporotic patients. This finding may provide a novel strategy for a treatment approach for osteoporosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29250156

https://www.spandidos-publications.com/10.3892/etm.2017.5369

Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage following renal ischemia-reperfusion injury.

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Journal of Pharmacology and Experimental Therapeutics “Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with increased rates of mortality. Currently, therapies to treat AKI are not available, so identification of new targets which, upon diagnosis of AKI, can be modulated to ameliorate renal damage is essential.

In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295, was designed, synthesized, and tested in vitro and in silico.

These data suggests that selective CB2 receptor activation could be a potential therapeutic target in the treatment for AKI.”

https://www.ncbi.nlm.nih.gov/pubmed/29187590

http://jpet.aspetjournals.org/content/early/2017/11/29/jpet.117.245522

Involvement of cannabinoid receptor type 2 in light-induced degeneration of cells from mouse retinal cell line in vitro and mouse photoreceptors in vivo.

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Experimental Eye Research

“Earlier studies showed that the expressions of the agonists of the cannabinoid receptors are reduced in the vitreous humor of patients with age-related macular degeneration (AMD), and the cannabinoid type 2 receptor is present in the retinas of rats and monkeys. The purpose of this study was to determine whether the cannabinoid type 2 receptor is involved in the light-induced death of cultured 661W cells, an immortalized murine retinal cell line, and in the light-induced retinal degeneration in mice.

Time-dependent changes in the expression and location of retinal cannabinoid type 2 receptor were determined by Western blot and immunostaining. The cannabinoid type 2 receptor was down-regulated in murine retinae and cone cells. In the in vitro studies, HU-308, a cannabinoidtype 2 receptor agonist, had a protective effect on the light-induced death of 661W cells, and this effect was attenuated by SR144528, a cannabinoid type 2 receptor antagonist.

Because the cannabinoid type 2 receptor is a G-protein coupled receptor and is coupled with Gi/o protein, we investigated the effects of the cAMP-dependent protein kinase (PKA). HU-308 and H89, a PKA inhibitor, deactivated PKA in retinal cone cells, and H89 also suppressed light-induced cell death. For the in vivo studies, a cannabinoid type 2 receptor agonist, HU-308, or an antagonist, SR144528, was injected intravitreally into mouse eyes before the light exposure. Electroretinography was used to determine the physiological status of the retinas. Injection of HU-308 improved the a- and b-waves of the ERGs and also the thickness of the outer nuclear layer of the murine retina after light exposure.

These findings indicate that the cannabinoid type 2 receptor is involved in the light-induced retinal damage through PKA signaling. Thus, activation of cannabinoidtype 2 receptor may be a therapeutic approach for light-associated retinal diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29133122

http://www.sciencedirect.com/science/article/pii/S0014483516304456?via%3Dihub

Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2 Receptors.

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“The mechanism of action of cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa L., is not completely understood. First assumed that the compound was acting via cannabinoid CB2 receptors (CB2Rs) it is now suggested that it interacts with non-cannabinoid G-protein-coupled receptors (GPCRs); however, CBD does not bind with high affinity to the orthosteric site of any GPCR.

To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB2R. Radioligand and non-radioactive homogeneous binding, intracellular cAMP determination and ERK1/2 phosphorylation assays were undertaken in heterologous systems expressing the human version of CB2R.

These results may help to understand CBD mode of action and may serve to revisit its therapeutic possibilities.”

https://www.ncbi.nlm.nih.gov/pubmed/29109685

https://www.frontiersin.org/articles/10.3389/fphar.2017.00744/full

Radioligands for Positron Emission Tomography Imaging of Cannabinoid type 2 Receptor.

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Journal of Labelled Compounds and Radiopharmaceuticals

“The cannabinoid type 2 (CB2) receptor is an immunomodulatory receptor mainly expressed in peripheral cells and organs of the immune system. The expression level of CB2 in the central nervous system under physiological conditions is negligible, however under neuroinflammatory conditions an upregulation of CB2 protein or mRNA mainly co-localized with activated microglial cells has been reported.

Consequently, CB2 agonists have been confirmed to play a role in neuroprotective and anti-inflammatory processes.

A suitable PET radioligand for imaging CB2 would provide an invaluable research tool to explore the role of CB2 receptor expression in inflammatory disorders. In this review, we provide a summary of so far published CB2 radioligands as well as their in vitro and in vivo binding characteristics.”

https://www.ncbi.nlm.nih.gov/pubmed/29110331

http://onlinelibrary.wiley.com/doi/10.1002/jlcr.3579/abstract

Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.

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“Inflammation is an important mediator of secondary neurological injury after traumatic brain injury (TBI). Endocannabinoids, endogenously produced arachidonate based lipids, have recently emerged as powerful anti-inflammatory compounds, yet the molecular and cellular mechanisms underlying these effects are poorly defined. Endocannabinoids are physiological ligands for two known cannabinoid receptors, CB1R and CB2R. In the present study, we hypothesized that selective activation of CB2R attenuates neuroinflammation and reduces neurovascular injury after TBI. Taken together, our findings support the development of selective CB2R agonists as a therapeutic strategy to improve TBI outcomes while avoiding the psychoactive effects of CB1R activation.”   https://www.ncbi.nlm.nih.gov/pubmed/29079445   http://www.sciencedirect.com/science/article/pii/S0889159117304774

“The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration. The first approved cannabinoid drugs were analogues of Δ9-tetrahydrocannabinol (Δ9-THC). Dronabinol is a natural isomer of THC that is found in the cannabis plant” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435344/

“Cannabinoid Receptor CB2 Is Involved in Tetrahydrocannabinol-Induced Anti-Inflammation against Lipopolysaccharide in MG-63 Cells. These results suggested that CB2 is involved in the THC-induced anti-inflammation”  https://www.hindawi.com/journals/mi/2015/362126/

“Cannabinoids as novel anti-inflammatory drugs. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders.  For several centuries, marijuana has been used as an alternative medicine in many cultures and, recently, its beneficial effects have been shown”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

“Cannabinoids as neuroprotective agents in traumatic brain injury.  Cannabinoids of all classes have the ability to protect neurons from a variety of insults that are believed to underlie delayed neuronal death after traumatic brain injury (TBI), including excitotoxicity, calcium influx, free radical formation and neuroinflammation.” https://www.ncbi.nlm.nih.gov/pubmed/15281893

“Effect of marijuana use on outcomes in traumatic brain injury. A positive THC screen is associated with decreased mortality in adult patients sustaining TBI.”  https://www.ncbi.nlm.nih.gov/pubmed/25264643