Tag Archives: CB2

Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveal a Mechanism for Regulation of Tumor Progression.

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“The G-protein-coupled chemokine receptor, CXCR4, generates signals that lead to cell migration, cell proliferation, and other survival mechanisms which result in the metastatic spread of primary tumor cells to distal organs.

Numerous studies have demonstrated that CXCR4 can form homodimers, or can heterodimerize with other GPCRs to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor.

Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells.

Simultaneous, agonist-dependent activation of CXCR4 and CB2 resulted in reduced CXCR4-mediated expression of phosphorylated ERK1/2, and ultimately, reduced cancer cell functions such as calcium mobilization and cellular chemotaxis.

Given that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells, as well as CXCR4-mediated migration of immune cells, it is therefore plausible that CXCR4 signaling can be silenced through a physical heterodimeric association with CB2, thereby inhibiting subsequent functions of CXCR4.

Taken together, the data illustrates a mechanism by which the cannabinoid system can negatively modulate CXCR4 receptor function, and perhaps, tumor progression.”

http://www.ncbi.nlm.nih.gov/pubmed/26841863

The molecular mechanism and effect of cannabinoid-2 receptor agonist on the blood-spinal cord barrier permeability induced by ischemia-reperfusion injury.

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“Previous studies have shown that modulation of the receptor-mediated endocannabinoid system during ischemia injury can induce potent neuroprotective effects.

However, little is known about whether cannabinoid-2 (CB2) receptor agonist would produce a protective effect on blood-spinal cord barrier (BSCB) during ischemia.

Taken together, all of these results suggested that JWH-015 might regulate the BSCB permeability and this effect could be related to paracellular and transcellular pathway.

And pharmacological CB2R ligands offer a new strategy for BSCB protection during ischemic injury.”

http://www.ncbi.nlm.nih.gov/pubmed/26835555

CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease

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“Parkinson’s disease (PD) is characterized by the degeneration of nigrostriatal dopamine neurons.

The endocannabinoid system consists of cannabinoid receptors, their ligands and enzymes for the synthesis and degradation of cannabinoids.

Our results suggest that targeting the cannabinoid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with glial activation, BBB disruption and peripheral immune cell infiltration.

In summary, we demonstrated that activation of the CB2 receptor inhibits BBB damage, the expression of iNOS and proinflammatory cytokines/chemokines in activated microglia, the infiltration of T cells and astroglial expression of MPO, resulting in the survival of dopamine neurons in vivo in the MPTP mouse model of PD.

Therefore, it is likely that targeting the CB2 receptor may have therapeutic value in the treatment of aspects of PD related to neuroinflammation.”

http://www.nature.com/emm/journal/v48/n1/full/emm2015100a.html

Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial.

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“Noncardiac chest pain is associated with poor quality of life and high care expenditure. The majority of noncardiac chest pain is either gastresophageal reflux disease related or due to esophageal motility disorders, and the rest are considered functional chest pain (FCP) due to central and peripheral hypersensitivity. Current treatment of FCP improves 40-50% of patients.

Cannabinoid receptors 1 (CB1 ) and 2 (CB2 ) modulate release of neurotransmitters; CB1 is located in the esophageal epithelium and reduces excitatory enteric transmission and potentially could reduce esophageal hypersensitivity.

We performed a prospective study to evaluate its effects on pain threshold, frequency, and intensity in FCP.

Dronabinol increased pain thresholds significantly (3.0 vs. 1.0; P = 0.03) and reduced pain intensity and odynophagia compared to placebo (0.18 vs. 0.01 and 0.12 vs. 0.01, respectively, P = 0.04).

Depression and anxiety scores did not differ between the groups at baseline or after treatment.

No significant adverse effects were observed.

In this novel study, dronabinol increased pain threshold and reduced frequency and intensity of pain in FCP. Further, large scale studies are needed to substantiate these findings.”

http://www.ncbi.nlm.nih.gov/pubmed/26822791

CB2 Cannabinoid Receptor Knockout in Mice Impairs Contextual Long-Term Memory and Enhances Spatial Working Memory.

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“Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids.

CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function.

Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas.”

http://www.ncbi.nlm.nih.gov/pubmed/26819779

Characterization of a novel adult murine immortalized microglial cell line and its activation by amyloid-beta.

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“Alzheimer’s disease is associated with amyloid-beta (Aβ)-induced microglia activation.

This pro-inflammatory response promotes neuronal damage, and therapies are sought to limit microglial activation.

The objective of this study was to characterize Aβ-induced activation of IMG cells, and here, we demonstrate the ability of cannabinoids to significantly reduce this inflammatory response.

Aβ-induced activation of IMG cells was suppressed by delta-9-tetrahydrocannabinol and the CB2-selective agonist JWH-015 in a time- and concentration-dependent manner.

IMG cells recapitulate key features of microglial cell activation. As an example of their potential pharmacological use, cannabinoids were shown to reduce activation of Aβ-induced iNOS gene expression.”

http://www.ncbi.nlm.nih.gov/pubmed/26819091

The Pharmacological Basis of Cannabis Therapy for Epilepsy.

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“Recently, cannabis has been suggested as a potential alternative therapy for refractory epilepsy, which affects 30% of epilepsy patients including children who do not respond to current medications.

There is a large unmet medical need for new antiepileptics for refractory epilepsy and conditions associated with refractory seizures that would not interfere with normal function.

The two chief cannabinoids are delta-9-tetrahyrdrocannabinol, the major psychoactive component of marijuana, and cannabidiol (CBD), the major non-psychoactive component of marijuana.

There are claims of clinical efficacy of CBD-predominant cannabis or medical marijuana for epilepsy, mostly from limited studies, surveys or case reports.

However, the mechanisms underlying the antiepileptic efficacy of cannabis remain unclear. This article highlights the pharmacological basis of cannabis therapy, with an emphasis on the endocannabinoid mechanisms underlying the emerging neurotherapeutics of CBD in epilepsy.

CBD is anticonvulsant, but it has a low affinity for the cannabinoid CB1 and CB2 receptors; therefore the exact mechanism by which it affects seizures remains poorly understood.

A rigorous clinical evaluation of pharmaceutical CBD products is needed to establish the safety and efficacy for the treatment of epilepsy.

Identification of mechanisms underlying the anticonvulsant efficacy of CBD is additionally critical to identify other potential treatment options.”

http://www.ncbi.nlm.nih.gov/pubmed/26787773

http://jpet.aspetjournals.org/content/early/2016/01/19/jpet.115.230151.long

http://www.thctotalhealthcare.com/category/epilepsy-2/

Effect of cannabinoids on CGRP release in the isolated rat lumbar spinal cord.

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“Cannabinoids produce analgesia through a variety of mechanisms.

It has been proposed that one mechanism is by modulating the release of CGRP in the spinal cord pain pathways.

Previous studies have reported that cannabinoids, particularly CB2 receptor agonists, can modulate CGRP release in the isolated rat spinal cord.

These results question the role of spinal cord cannabinoid receptors in the regulation of CGRP signalling.”

http://www.ncbi.nlm.nih.gov/pubmed/26762784

Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non-small cell lung cancer by downregulation of EGFR pathway.

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“JWH-015, a cannabinoid receptor 2 (CB2) agonist has tumor regressive property in various cancer types.

These data confer the impact of this cannabinoid on anti-proliferative and anti-tumorigenic effects, thus enhancing our understanding of its therapeutic efficacy in NSCLC.

Our findings open new avenues for cannabinoid receptor CB2 agonist-JWH-015 as a novel and potential therapeutic target based on EGFR downregulation mechanisms in NSCLC.”

http://www.ncbi.nlm.nih.gov/pubmed/26741322

Therapy with a Selective Cannabinoid Receptor Type 2 Agonist Limits Albuminuria and Renal Injury in Mice with Type 2 Diabetic Nephropathy.

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“A critical involvement of the endocannabinoid/cannabinoid receptor system in diabetes and its complications has been recognized.

Experimental evidence suggested that activation of the cannabinoid receptor type 2 (CB2), which is expressed in the kidney by podocytes and inflammatory cells, had a protective role in early streptozotocin-induced type 1 diabetes in mice.

In this study, we investigated the effects of a CB2 agonist given at a phase of overt disease on renal functional and structural changes in BTBR ob/ob mice, a model of type 2 diabetic nephropathy.

These results suggest that CB2 agonism is a potential option to be added to the available therapeutic armamentarium for type 2 diabetic nephropathy.”

http://www.ncbi.nlm.nih.gov/pubmed/26646377