Category Archives: Endocannabinoid System

Cannabinoid receptors in mantle cell lymphoma

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“Mantle cell lymphoma (MCL) is a non-curable B cell lymphoma that in several independent studies have been shown to express higher levels of CB1 and CB2 than non-malignant B cells.

The endocannabinoid system is dysregulated in many types of cancer and is involved in the regulation of survival and proliferation of cancer cells and cancer stem cells, in cancer metabolism, as well as in pro-metastatic events such as angiogenesis, migration and invasion.

Previous in vitro studies of MCL cell lines and primary ex vivo isolated tumor cells have demonstrated that high concentrations of cannabinoid receptor ligands induced proliferation arrest and programmed cell death.

All together, the data suggest that perturbations in the endocannabinoid system participate in the regulation of multi-functional cell responses regarding proliferation, migration and cell death control.

Therefore, it can be concluded that further studies on pharmacological modulation of endocannabinoid accumulation and/or signaling offers an interesting option for novel anti-lymphoma therapy.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353235/

Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma.

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“We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)).

In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated.

The present data suggest that targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.”

http://www.ncbi.nlm.nih.gov/pubmed/16936228

Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma.

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“We have earlier reported overexpression of the central and peripheral cannabinoid receptors CB1 and CB2 in mantle cell lymphoma (MCL), a B cell non-Hodgkin lymphoma.

In this study, treatment with cannabinoid receptor ligands caused a decrease in viability of MCL cells, while control cells lacking CB1 were not affected.

Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL.” http://www.ncbi.nlm.nih.gov/pubmed/16337199

“In conclusion, we have found that cannabinoid receptor ligands induce decreased viability, growth suppression and cell death by apoptosis in MCL cells, which express high levels of the CB1 receptor and moderate levels of CB2.

The current results in vitro suggest that CB1/CB2 ligands should be considered as agents for the treatment of MCL.”  http://onlinelibrary.wiley.com/doi/10.1016/j.febslet.2005.11.020/full

Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: growth inhibition by receptor activation.

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“Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL).

In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type.

Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2.”

http://www.ncbi.nlm.nih.gov/pubmed/18546271

The role of cannabinoid receptors and the endocannabinoid system in mantle cell lymphoma and other non-Hodgkin lymphomas.

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“The initiating oncogenic event in mantle cell lymphoma (MCL) is the translocation of cyclin D1, t(11;14)(q13;q32). However, other genetic aberrations are necessary for an overt lymphoma to arise. Like other B cell lymphomas, MCL at some points during the oncogenesis is dependent on interactions with other cells and factors in the microenvironment.

The G protein coupled receptors cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed at low levels on non-malignant lymphocytes and at higher levels in MCL and other lymphoma subtypes.

In this review we give an overview of what is known on the role of the cannabinoid receptors and their ligands in lymphoma as compared to non-malignant T and B lymphocytes.

In MCL cannabinoids mainly reduce cell proliferation and induce cell death.

Importantly, our recent findings demonstrate that cannabinoids may induce either apoptosis or another type of programmed cell death, cytoplasmic vacuolation/paraptosis in MCL.”

http://www.ncbi.nlm.nih.gov/pubmed/22024769

Cannabis for refractory psoriasis-high hopes for a novel treatment and a literature review.

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“Psoriasis is a common skin disorder characterized by hyper proliferation of keratinocytes. Although the exact pathophysiology of psoriasis is not entirely understood, immune system and its interaction with nervous system has been postulated and investigated as the underlying mechanism. The interaction between these two systems through cholinergic anti-inflammatory pathway and also endocannabinoid system, may suggest cannabinoids as potential addition to anti-psoriatic armamentarium.”

http://www.ncbi.nlm.nih.gov/pubmed/27164964

http://www.thctotalhealthcare.com/category/psoriasis/

Expression analysis of cannabinoid receptors 1 and 2 in B cells during pregnancy and their role on cytokine production.

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“The endocannabinoid system consists in a family of lipids that binds to and activates cannabinoid receptors. There are two receptors so far described, the cannabinoid receptor 1 (CB1) and 2 (CB2).

In the context of pregnancy, the endocannabinoid system was shown participates in different key aspects of reproductive events. B-lymphocytes are pleiotropic cells belonging to the adaptive arm of the immune system. Besides immunoglobulin production, B-lymphocytes were recently shown to be actively involved in antigen presentation as well as cytokine production, thus playing a central role in immunity.

In this study we first aimed to characterize the expression of CB1 and CB2 receptors in B cells during pregnancy and then analyze the impact of their activation in term of cytokine production by B cells from pregnant and non-pregnant mice.

We observed that the expression of CB1 and CB2 receptors in B-lymphocytes is differentially regulated during pregnancy. While CB2 expression is down regulated CB1 is augmented in B-lymphocytes of pregnant mice.

Additionally, the treatment of activated B-lymphocytes with specific CB1 and CB2 agonists, showed a different response in term of cytokine production. Particularly, CB1 against boosted the production of the anti-inflammatory cytokine IL-10 by activated B-lymphocytes from pregnant mice.”

http://www.ncbi.nlm.nih.gov/pubmed/27163857

A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease.

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“Huntington’s disease (HD) is a neurodegenerative disease for which there is no curative treatment available. Given that the endocannabinoid system is involved in the pathogenesis of HD mouse models, stimulation of specific targets within this signaling system has been investigated as a promising therapeutic agent in HD.

We conducted a double-blind, randomized, placebo-controlled, cross-over pilot clinical trial with Sativex®, a botanical extract with an equimolecular combination of delta-9-tetrahydrocannabinol and cannabidiol. Both Sativex® and placebo were dispensed as an oral spray, to be administered up to 12 sprays/day for 12 weeks.

The primary objective was safety, assessed by the absence of more severe adverse events (SAE) and no greater deterioration of motor, cognitive, behavioral and functional scales during the phase of active treatment. Secondary objectives were clinical improvement of Unified Huntington Disease Rating Scale scores.

Twenty-six patients were randomized and 24 completed the trial. After ruling-out period and sequence effects, safety and tolerability were confirmed. No differences on motor (p = 0.286), cognitive (p = 0.824), behavioral (p = 1.0) and functional (p = 0.581) scores were detected during treatment with Sativex® as compared to placebo. No significant molecular effects were detected on the biomarker analysis.

Sativex® is safe and well tolerated in patients with HD, with no SAE or clinical worsening.

No significant symptomatic effects were detected at the prescribed dosage and for a 12-week period. Also, no significant molecular changes were observed on the biomarkers.

Future study designs should consider higher doses, longer treatment periods and/or alternative cannabinoid combinations. Clincaltrals.gov identifier: NCT01502046.”

http://www.ncbi.nlm.nih.gov/pubmed/27159993

Cannabinoid receptor genes.

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“Cannabinoids are the constituents of the marijuana plant (cannabis sativa) of which the major active ingredient is delta-9-tetrahydrocannabinol (delta 9-THC). Rapid progress has been achieved in marijuana research in the last five years than in the thousands of years that marijuana has been used in human history.

For many decades therefore, research on the molecular and neurobiological bases of the physiological and neurobehavioral effects of marijuana was hampered by the lack of specific research tools and technology. The situation has started to change with the availability of molecular probes and other recombinant molecules that have led to major advances.

Recent advances include the cloning of the cDNA sequences encoding the rat, human and the mouse peripheral and CNS cannabinoid receptors. In addition a putative ligand, anandamide, thought to represent the endogenous cannabis-like substance that binds the cannabinoid receptors, has been isolated from the brain.

This achievement has opened a whole new neurochemical system particularly as the physiological and pharmacological properties of anandamide indicate a possible neuromodulatory or neurotransmitter role.

The recent demonstration of a potent and selective antagonist for CBl receptors may become an important and powerful investigative tool. Future progress on the neurobiology of cannabinoid research may include data on the use of antisense strategies and gene targeting approach to further understand the mechanism(s) of action of cannabinoids which has been slow to emerge.

We conclude that these are exciting times for cannabis research which has given us anandamide–a substance of inner bliss.”

http://www.ncbi.nlm.nih.gov/pubmed/8804112

The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

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“Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder.

The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells.

The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children.

In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls.

This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.

This study demonstrates a biomolecular effect of GcMAF in BMDMs from autistic patients, providing further evidence for a positive use of this molecule in autism treatment. It also seems likely that the CB2R is a potential therapeutic target for Autism and autism spectrum disorders (ASDs) interventions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996516/