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

Synthetic cannabinoid receptor agonists and antagonists: implication in CNS disorders.

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“Since the discovery of the cannabinoid receptors, numerous studies associate the endocannabinoid system with several physiological and pathological processes including cancer, appetite, fertility, memory, neuropathic and inflammatory pain, obesity, and neurodegenerative diseases.

Over the last two decades, several researches have been dedicated extensively on the cannabinoid receptors ligands since the direct activation of cannabinoid receptors results in several beneficial effects, in the brain and in the periphery.

During past years, cannabinoid CB1 and CB2 receptor ligands from plants or lab were rapidly developed and then various new structures were reported to be cannabinoids.

The CB1 and CB2 receptor ligands offer several therapeutic opportunities for several CNS-related diseases.

Based on the scientific literature, this review provides an overview of CB1 and CB2 receptor synthetic ligands obtained from drug research and in particular those synthesized for therapeutic purposes and potential clinical applications for central nervous system disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/27193072

Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis.

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“The endocannabinoid system (ECS) exerts key roles in the development of liver fibrosis and fatty liver, two diseases that promote the development of hepatocellular carcinoma (HCC).

Although cannabinoids exert potent antitumour effects in vitro, the contribution of the ECS to carcinogenesis in vivo remains elusive.

CONCLUSIONS:

Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis and may provide novel therapeutic targets.”

http://www.ncbi.nlm.nih.gov/pubmed/27196571

Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent

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“Breast cancer is the leading cause of cancer-related deaths among women aged 34–50 worldwide, and is the most commonly diagnosed metastasizing tumor in women of all ages. Despite advances in understanding breast cancer as a disease, there remains a critical need for novel disease-modifying therapeutics.

Nonspecific cannabinoids, cannabinoid receptor 2 (CB2)-selective, as well as cannabinoid receptor 1 (CB1)-selective compounds have yielded similar antitumor results in several tumor models. The lack of neuronal expression of CB2 receptors precludes CB2 selective compounds from inducing the psychotropic effects that typically accompany CB1 activation.

 Our group and others have shown that CB2 agonists displaying selectivity for the CB2 receptor can decrease tumor cell viability and significantly attenuate cancer-induced bone pain without displaying psychoactive or addictive properties.

…antitumor effects of cannabinoids have been demonstrated in a variety of tumor models…

The antiproliferative effects of a CB2 agonist along with our previous work demonstrating significant efficacy in inhibiting bone cancer pain and slowing bone loss in a murine model of advanced breast cancer strongly suggest that CB2 agonists should be investigated in humans as adjunct therapy for advanced stages of breast cancer.

 Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2), have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems.
The results of this work characterize the actions of a CB2-selective agonist on breast cancer cells in a syngeneic murine model representing how a clinical presentation of cancer progression and metastasis may be significantly modulated by a G-protein-coupled receptor.
Several groups have shown that both nonselective cannabinoid and CB2-specific compounds decrease breast cancer viability in vitro and in vivo: Δ9-tetrahydrocannabinol and CB2-selective agonist, JWH-133, have been demonstrated to exert considerable antitumoral effects…”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847606/

Phytocannabinoids and cannabimimetic drugs: recent patents in central nervous system disorders.

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“Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs.

These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors.

Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases.

The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression.

CONCLUSIONS:

Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27184693

Neuroprotection by Cannabinoids in Huntington’s Disease

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“A Double Blind, Randomized, Cross Over, Placebo Controlled Phase 2 Clinical Trial to Asses Neuroprotection by Cannabinoids in Huntington’s Disease.”

ClinicalTrials.gov

“Huntington’s disease (HD) is a progressive neurodegenerative disorder, related to an abnormal expansion of CAG triplets in the huntingtin gene, characterized by motor, cognitive and behavioral abnormalities, without known effective symptomatic treatment and without known disease slowing strategy. The most severe neuropathological lesions observed in HD take place in the striatum, one brain area important in motor control and rich in cannabinoid receptors (CBR). CBR are subdivided in two classes: CB1R are located in neurons and play a role in neuronal function; CB2R in brain are located mostly in microglia and modulate neuroinflammation.

CBR disappear early in the course of HD, before there is a massive drop out of cells in the striatum. Cannabinoid transmission is also an early event in brains of animal models of HD. In R6/2 mice, which carry large CAG expansions and develop an early and severe HD phenotype the suppression of the CB1R gene further accelerate the development of a severe clinical syndrome and the characteristic brain inclusions and abnormalities of synaptic density. R6/2 treated mice treated with cannabinoids improve their clinical phenotype, their brain lesions, the synaptic density and the levels of BNDF, a neurotrophic factor which enhances survival and resistance of striatal neurons.

Preliminary studies of cannabinoids in patients with HD have shown that these compounds are safe in these patients.”

https://clinicaltrials.gov/show/NCT01502046

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