Cannabinoid receptors as therapeutic targets for autoimmune diseases: where do we stand?

Drug Discovery Today

“Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).”

https://www.ncbi.nlm.nih.gov/pubmed/31158514

https://www.sciencedirect.com/science/article/pii/S1359644618304847?via%3Dihub

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A selective CB2 agonist protects against the inflammatory response and joint destruction in collagen-induced arthritis mice.

Biomedicine & Pharmacotherapy

“Rheumatoid arthritis (RA) is a chronic, inflammatory, synovitis-dominated systemic disease with unknown etiology. RA is characterized by the involvement of multiple affected joints, symmetry, and invasive arthritis of the limbs, which can lead to joint deformity, cartilage destruction, and loss of function. Cannabinoid receptor 2 (CB2) has potent immunomodulatory and anti-inflammatory effects and is predominantly expressed in non-neuronal tissues. In the current study, the role of CB2 in the process of inflammatory bone erosion in RA was examined. The selective agonist or high-affinity ligand of CB2 (4-quinolone-3-carboxamides CB2 agonist, 4Q3C CB2agonist, 4Q3C) significantly reduced the severity of arthritis, decreased histopathological findings, and markedly reduced bone erosion in collagen-induced arthritis (CIA) mice. In addition, 4Q3C prevented an increase in the nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio and inhibited the formation of osteoclasts in CIA mice. Furthermore, the expression of tumor necrosis factor-alpha, interleukin-1β, cyclooxygenase-2, and inducible nitric oxide synthase was lower in 4Q3C-treated CIA mice than in control CIA mice. Micro-computed tomography corroborated the finding that 4Q3C reduced joint destruction. These data clearly indicate that the CB2-selective agonist, 4Q3C, may have anti-inflammatory and anti-osteoclastogenesis effects in RA and may be considered to be a novel treatment for RA.”

https://www.ncbi.nlm.nih.gov/pubmed/31154267

https://www.sciencedirect.com/science/article/pii/S0753332219307528?via%3Dihub

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Joints for joints: cannabinoids in the treatment of rheumatoid arthritis.

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“An increasing number of patients with rheumatoid arthritis (RA) are using cannabis to treat their symptoms, although systematic studies regarding efficacy in RA are lacking. Within this review we will give an overview on the overall effects of cannabinoids in inflammation and why they might be useful in the treatment of RA.

RECENT FINDINGS:

Peripherally, cannabinoids show anti-inflammatory effects by activating cannabinoid type 2 receptors (CB2) which decrease cytokine production and immune cell mobilization. In contrast, cannabinoid type 1 receptor (CB1) activation on immune cells is proinflammatory while CB1 antagonism provides anti-inflammatory effects by increasing β2-adrenergic signaling in the joint and secondary lymphoid organs. In addition, the nonpsychotropic cannabinoid, cannabidiol (CBD) demonstrated antiarthritic effects independent of cannabinoid receptors. In addition to controlling inflammation, cannabinoids reduce pain by activating central and peripheral CB1, peripheral CB2 receptors and CBD-sensitive noncannabinoid receptor targets.

SUMMARY:

Cannabinoids might be a suitable treatment for RA, but it is important to target the right receptors in the right place. For clinical studies, we propose a combination of a CB2 agonist to decrease cytokine production, a peripheral CB1 antagonist to prevent detrimental CB1 signaling and to support anti-inflammatory effects of CB2 via activation of β2-adrenergic receptors and CBD to induce cannabinoid-receptor-independent anti-inflammatory effects.”

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[MEDICAL CANNABIS – A SOURCE FOR A NEW TREATMENT FOR AUTOIMMUNE DISEASE?].

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“Medical uses of Cannabis sativa have been known for over 6,000 years. Nowadays, cannabis is mostly known for its psychotropic effects and its ability to relieve pain, even though there is evidence of cannabis use for autoimmune diseases like rheumatoid arthritis centuries ago. The pharmacological therapy in autoimmune diseases is mainly based on immunosuppression of diffefent axes of the immune system while many of the drugs have major side effects. In this review we set out to examine the rule of Cannabis sativa as an immunomodulator and its potential as a new treatment option. In order to examine this subject we will focus on some major autoimmune diseases such as diabetes type I and rheumatoid arthritis.”

https://www.ncbi.nlm.nih.gov/pubmed/27215114

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Cannabinoid receptor 2 agonist prevents local and systemic inflammatory bone destruction in rheumatoid arthritis.

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“Cannabinoid receptor 2 (CB2) has been implicated as an important clinical regulator of inflammation and malignant osteolysis. Here, we observed that CB2 expression was markedly higher in the collagen-induced arthritis (CIA) mice synovium and bone tissues than in the non-inflamed synovium and bone tissues. We found that JWH133 ameliorates pathologic bone destruction in CIA mice via the inhibition of osteoclastogenesis and modulation of inflammatory responses, thereby highlighting its potential as a treatment for human rheumatoid arthritis.”

https://www.ncbi.nlm.nih.gov/pubmed/30508319

https://onlinelibrary.wiley.com/doi/abs/10.1002/jbmr.3637

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Study of cannabinoid receptor 2 Q63R gene polymorphism in Lebanese patients with rheumatoid arthritis.

 

“The cannabinoid (CB) receptor 2, primarily expressed in immune cells, was shown to play important immune-regulatory functions. In particular, the CB2-R63 functional variant has been shown to alter the ability of the CB2 receptor to exert its inhibitory function on T lymphocytes.

The aim of this study was to investigate the association between a common dinucleotide polymorphism, Q63R, in the cannabinoid receptor 2 gene (CNR2) and rheumatoid arthritis (RA) in the Lebanese population.

One hundred five unrelated Lebanese RA patients and one hundred five controls from different Lebanese governorates were recruited in this study. Genomic DNA was extracted, polymerase chain reaction was performed, and CNR2 was genotyped in a blinded fashion. The χ2 test was used to determine the differences in genotypes and allele frequencies. CNR2 genotyping showed significantly higher frequencies of the CB2-R63 variant (allele frequencies, P < 0.00001; genotype distribution, P < 0.00001) in RA patients when compared with healthy controls. Moreover, RR carriers had more than 10-fold risk for developing RA (OR = 10.8444, 95% CI = 5.0950-23.0818; P < 0.0001), and QR carriers had more than 3-fold risk (OR = 3.8667, 95% CI = 1.7886-8.3591; P = 0.0006) as compared with QQ carriers.

Our preliminary results suggest a role of CB2-Q63R gene polymorphism in the etiology of RA, thus supporting its potential use as a pharmacological target for selective agonists in clinical practice.”

https://www.ncbi.nlm.nih.gov/pubmed/30032418

https://link.springer.com/article/10.1007%2Fs10067-018-4217-9

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Is cannabis an effective treatment for joint pain?

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“Cannabis has been used to treat pain for thousands of years.

However, since the early part of the 20th century, laws restricting cannabis use have limited its evaluation using modern scientific criteria. Over the last decade, the situation has started to change because of the increased availability of cannabis in the United States for either medical or recreational purposes, making it important to provide the public with accurate information as to the effectiveness of the drug for joint pain among other indications.

The major psychotropic component of cannabis is Δ9-tetrahydrocannabinol (THC), one of some 120 naturally occurring phytocannabinoids. Cannabidiol (CBD) is another molecule found in herbal cannabis in large amounts. Although CBD does not produce psychotropic effects, it has been shown to produce a variety of pharmacological effects. Hence, the overall effects of herbal cannabis represent the collective activity of THC, CBD and a number of minor components.

The action of THC is mediated by two major G-protein coupled receptors, cannabinoid receptor type 1 (CB1) and CB2, and recent work has suggested that other targets may also exist. Arachidonic acid derived endocannabinoids are the normal physiological activators of the two cannabinoid receptors.

Natural phytocannabinoids and synthetic derivatives have produced clear activity in a variety of models of joint pain in animals. These effects are the result of both inhibition of pain pathway signalling (mostly CB1) and anti-inflammatory effects (mostly CB2). There are also numerous anecdotal reports of the effectiveness of smoking cannabis for joint pain.

Indeed, it is the largest medical request for the use of the drug. However, these reports generally do not extend to regulated clinical trials for rheumatic diseases. Nevertheless, the preclinical and human data that do exist indicate that the use of cannabis should be taken seriously as a potential treatment of joint pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28967368

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Endocannabinoids in arthritis: current views and perspective.

International Journal of Rheumatic Diseases

“Preclinical and clinical studies using cannabis-based therapy have been shown to provide both analgesia and anti-inflammatory effects, with an overall alleviation of clinical symptoms in animal models of arthritis, highlighting its promising therapeutic application for humans. Despite this, the development of cannabis-based therapeutics remains in its infancy, with further investigation into its efficacy and safety profile in patients still required. This synopsis reviews the various components of the endocannabinoid system in health and disease and their potential as therapeutic targets.”

https://www.ncbi.nlm.nih.gov/pubmed/28736968

http://onlinelibrary.wiley.com/doi/10.1111/1756-185X.13146/abstract

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Comparative in silico analyses of Cannabis sativa, Prunella vulgaris and Withania somnifera compounds elucidating the medicinal properties against rheumatoid arthritis

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“From last decade, there has been progressive improvement in computational drug designing. Several diseases are being cured from different plant extracts and products.

Rheumatoid arthritis (RA) is the most shared disease among auto-inflammatory diseases. Tumor necrosis factor (TNF)-α is associated with RA pathway and has adverse effects.

Extensive literature review showed that plant species under study (Cannabis sativa, Prunella vulgaris and Withania somnifera) possess anti-inflammatory, anti-arthritic and anti-rheumatic properties.

13 anti-inflammatory compounds were characterized and filtered out from medicinal plant species and analyzed for RA by targeting TNF-α through in silicoanalyses. By using ligand based pharmacophore generation approach and virtual screening against natural products libraries we retrieved twenty unique molecules that displayed utmost binding affinity, least binding energies and effective drug properties. The docking analyses revealed that Ala-22, Glu-23, Ser-65, Gln-67, Tyr-141, Leu-142, Asp-143, Phe-144 and Ala-145 were critical interacting residues for receptor-ligand interactions.

It is proposed that the RA patients should use reported compounds for the prescription of RA by targeting TNF-α. This report is opening new dimensions for designing innovative therapeutic targets to cure RA.”

https://www.ncbi.nlm.nih.gov/pubmed/28472734

http://www.sciencedirect.com/science/article/pii/S1093326317302735

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Medical Cannabis – another piece in the mosaic of autoimmunity?

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“Legalization of cannabis’ medicinal use is rapidly increasing worldwide, raising the need to evaluate medical implications of cannabis. Currently evidence supports cannabis and its active ingredients as an immune-modulating agents, affecting T-cells, B-cells, Monocytes and Microglia-cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. Due to the supporting evidence of cannabinoids as an immune-modulating agent, research focusing on cannabinoids and autoimmunity has emerged. Several clinical trials in multiple sclerosis, inflammatory bowel disease and fibromyalgia suggest cannabis’ effectiveness as an immune-modulator. However, contradicting results and lack of large scale clinical trials obscure these results. Though lacking clinical research, in-vitro and in-vivo experiments in rheumatoid arthritis, diabetes type 1 and systemic sclerosis, demonstrate a correlation between disease activity and cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/27859024

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