Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB 2 receptor in the arthritis progression and pain: an updated review

“Over the last several decades, the percentage of patients suffering from different forms of arthritis has increased due to the ageing population and the increasing risk of civilization diseases, e.g. obesity, which contributes to arthritis development. Osteoarthritis and rheumatoid arthritis are estimated to affect 50-60% of people over 65 years old and cause serious health and economic problems. Currently, therapeutic strategies are limited and focus mainly on pain attenuation and maintaining joint functionality. First-line therapies are nonsteroidal anti-inflammatory drugs; in more advanced stages, stronger analgesics, such as opioids, are required, and in the most severe cases, joint arthroplasty is the only option to ensure joint mobility.

Cannabinoids, both endocannabinoids and synthetic cannabinoid receptor (CB) agonists, are novel therapeutic options for the treatment of arthritis-associated pain. CB1 receptors are mainly located in the nervous system; thus, CB1 agonists induce many side effects, which limit their therapeutic efficacy. On the other hand, CB2 receptors are mainly located in the periphery on immune cells, and CB2 modulators exert analgesic and anti-inflammatory effects in vitro and in vivo. In the current review, novel research on the cannabinoid-mediated analgesic effect on arthritis is presented, with particular emphasis on the role of the CB2 receptor in arthritis-related pain and the suppression of inflammation.”

https://pubmed.ncbi.nlm.nih.gov/34050525/

“Cannabinoids not only alleviate joint hyperalgesia but also may help to prevent joint damage, chronic pain development and disease progression.”

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β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19

Frontiers in Pharmacology (@FrontPharmacol) | Twitter“Coronavirus disease (COVID-19), caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing pandemic and presents a public health emergency. It has affected millions of people and continues to affect more, despite tremendous social preventive measures. Identifying candidate drugs for the prevention and treatment of COVID-19 is crucial. The pathogenesis and the complications with advanced infection mainly involve an immune-inflammatory cascade. Therefore, therapeutic strategy relies on suppressing infectivity and inflammation, along with immune modulation.

One of the most promising therapeutic targets for the modulation of immune-inflammatory responses is the endocannabinoid system, particularly the activation of cannabinoid type 2 receptors (CB2R), a G-protein coupled receptor which mediates the anti-inflammatory properties by modulating numerous signaling pathways. To pharmacologically activate the CB2 receptors, a naturally occurring cannabinoid ligand, beta-caryophyllene (BCP), received attention due to its potent anti-inflammatory, antiviral, and immunomodulatory properties. BCP is recognized as a full selective functional agonist on CB2 receptors and produces therapeutic effects by activating CB2 and the nuclear receptors, peroxisome proliferator-activated receptors (PPARs).

BCP is regarded as the first dietary cannabinoid with abundant presence across cannabis and non-cannabis plants, including spices and other edible plants. BCP showed tissue protective properties and favorably modulates numerous signaling pathways and inhibits inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Based on its pharmacological properties, molecular mechanisms, and the therapeutic potential of BCP as an immunomodulator, anti-inflammatory, organ-protective, and antiviral, we hypothesize that BCP could be a promising therapeutic and/or preventive candidate to target the triad of infection, immunity, and inflammation in COVID-19. In line with numerous studies that proposed the potential of cannabinoids in COVID-19,

BCP may be a novel candidate compound for pharmaceutical and nutraceutical development due to its unique functional receptor selectivity, wide availability and accessibility, dietary bioavailability, nonpsychoactivity, and negligible toxicity along with druggable properties, including favorable pharmacokinetic and physicochemical properties. Based on reasonable pharmacological mechanisms and therapeutic properties, we speculate that BCP has potential to be investigated against COVID-19 and will inspire further preclinical and clinical studies.”

https://pubmed.ncbi.nlm.nih.gov/34054510/

“Over the past few months, it has been suggested that modulation of the endocannabinoid system by cannabinoids, including cannabidiol, could be useful in prophylaxis and treatment of COVID-19 and may improve prognosis. Recently, extract of Cannabis sativa containing phytocannabinoids and terpenes were shown to modulate the inflammatory mediators in alveolar epithelial cells (A549) in COVID-19-associated inflammation and suggested that the phytocannabinoid mix formulation exerted better activity in comparison with individual fractions from cannabis. Many cannabinoids, including cannabidiol, have been suggested for their possible potential as preventive agents or therapeutic adjuvants with other agents in targeting the trinity of infection, inflammation, and immunity in COVID-19.”

https://www.frontiersin.org/articles/10.3389/fphar.2021.590201/full

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

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Cannabinoid Receptor Type-2 in B Cells Is Associated with Tumor Immunity in Melanoma

cancers-logo“Agents targeting the endocannabinoid system (ECS) have gained attention as potential cancer treatments. Given recent evidence that cannabinoid receptor 2 (CB2R) regulates lymphocyte development and inflammation, we performed studies on CB2R in the immune response against melanoma. Analysis of The Cancer Genome Atlas (TCGA) data revealed a strong positive correlation between CB2R expression and survival, as well as B cell infiltration in human melanoma. In a murine melanoma model, CB2R expression reduced the growth of melanoma as well as the B cell frequencies in the tumor microenvironment (TME), compared to CB2R-deficient mice. In depth analysis of tumor-infiltrating B cells using single-cell RNA sequencing suggested a less differentiated phenotype in tumors from Cb2r-/- mice. Thus, in this study, we demonstrate for the first time a protective, B cell-mediated role of CB2R in melanoma. This gained insight might assist in the development of novel, CB2R-targeted cancer therapies.”

https://pubmed.ncbi.nlm.nih.gov/33923757/

“In this study we investigated the role of cannabinoid receptor 2 (CB2R) on immune cells in melanoma and found significantly improved overall survival in patients with high intra-tumoral CB2R gene expression. In human melanoma, CB2R is predominantly expressed in B cells, as shown using a previously published single-cell RNA sequencing (scRNA-seq) dataset and by performing RNAscope. In a murine melanoma model, tumor growth was enhanced in CB2R-deficient mice. In-depth analysis of tumor-infiltrating lymphocytes using scRNA-seq showed less differentiated B cells in CB2R-deficient tumors, favoring the induction of regulatory T cells (Treg) and an immunosuppressive tumor microenvironment. Taken together, these data indicate a central role of CB2R on B cells in regulating tumor immunity. These results contribute to the understanding of the role of CB2R in tumor immunity and facilitate the development of new CB2R-targeted anti-cancer drugs.”

https://www.mdpi.com/2072-6694/13/8/1934

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Cannabinoids pharmacological effects are beyond the palliative effects: CB2 cannabinoid receptor agonist induced cytotoxicity and apoptosis in human colorectal cancer cells (HT-29)

SpringerLink“Colorectal cancer (CRC) is between the top three occurring cancers worldwide. The anticancer effects of Cannabinoid receptor 2 (CB2) agonist (GW833972A) in the presence and absence of its inverse agonist (SR144528) on Human colorectal adenocarcinoma cells (HT-29) was investigated. Following cell viability assays on HT-29 and HFF cells, the molecular mechanism(s) of cytotoxicity and apoptotic pathways of cell death were analyzed. The anticancer effects of CB2 agonist were measured with tumor cell migration and colony-forming assays. Real-time PCR and Western blotting techniques were used to examine any alterations in the expression of apoptotic genes. A concentration and time-dependent cytotoxicity of CB2 agonist with IC50 value of 24.92 ± 6.99 μM was obtained. The rate of lipid peroxidation was elevated, while the TNF-α concentration was declined, significantly (p < 0.05). CB2 agonist (50 μM) reduced the colony-forming capability by 83% and tumor cell migration by 50%. Apoptotic effects of CB2 agonist were revealed with the increase of apoptotic cells in Acridine orange/Ethidium bromide staining, clear DNA fragmentation, pro-apoptotic genes and proteins upregulation (Caspase-3 and p53), and significant downregulation of anti-apoptotic Bcl-2. All assessments demonstrated that CB2 agonist-induced effects were reversed by CB2 inverse agonist. These data suggest that CB2 agonists at micro-molar concentrations might be considered in the CRC treatment, and their effectiveness attributes to the apoptosis induction via upregulation of caspase-3 and p53 and downregulation of Bcl-2.”

https://pubmed.ncbi.nlm.nih.gov/33886060/

https://link.springer.com/article/10.1007/s11010-021-04158-6

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CB2 receptor-selective agonists as candidates for targeting infection, inflammation, and immunity in SARS-CoV-2 infections

“The COVID-19 pandemic caused by SARS-CoV-2 is a deadly disease afflicting millions. The pandemic continues affecting population due to nonavailability of drugs and vaccines. The pathogenesis and complications of infection mainly involve hyperimmune-inflammatory responses. Thus, therapeutic strategies rely on repurposing of drugs aimed at reducing infectivity and inflammation and modulate immunity favourably.

Among, numerous therapeutic targets, the endocannabinoid system, particularly activation of cannabinoid type-2 receptors (CB2R) emerged as an important one to suppress the hyperimmune-inflammatory responses. Recently, potent antiinflammatory, antiviral and immunomodulatory properties of CB2R selective ligands of endogenous, plant, and synthetic origin were showed mediating CB2R selective functional agonism.

CB2R activation appears to regulate numerous signaling pathways to control immune-inflammatory mediators including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Many CB2R ligands also exhibit off-target effects mediating activation of PPARs, opioids, and TRPV, suggestive of adjuvant use with existing drugs that may maximize efficacy synergistically and minimize therapeutic doses to limit adverse/ side effects.

We hypothesize that CB2R agonists, due to immunomodulatory, antiinflammatory, and antiviral properties may show activity against COVID-19. Based on the organoprotective potential, relative safety, lack of psychotropic effects, and druggable properties, CB2R selective ligands might make available promising candidates for further investigation.”

https://pubmed.ncbi.nlm.nih.gov/33190277/

https://onlinelibrary.wiley.com/doi/10.1002/ddr.21752

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Protective Effects of ( E)-β-Caryophyllene (BCP) in Chronic Inflammation

nutrients-logo“(E)-β-caryophyllene (BCP) is a bicyclic sesquiterpene widely distributed in the plant kingdom, where it contributes a unique aroma to essential oils and has a pivotal role in the survival and evolution of higher plants.

Recent studies provided evidence for protective roles of BCP in animal cells, highlighting its possible use as a novel therapeutic tool.

Experimental results show the ability of BCP to reduce pro-inflammatory mediators such as tumor necrosis factor-alfa (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus ameliorating chronic pathologies characterized by inflammation and oxidative stress, in particular metabolic and neurological diseases.

Through the binding to CB2 cannabinoid receptors and the interaction with members of the family of peroxisome proliferator-activated receptors (PPARs), BCP shows beneficial effects on obesity, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) liver diseases, diabetes, cardiovascular diseases, pain and other nervous system disorders.

This review describes the current knowledge on the biosynthesis and natural sources of BCP, and reviews its role and mechanisms of action in different inflammation-related metabolic and neurologic disorders.”

https://pubmed.ncbi.nlm.nih.gov/33114564/

https://www.mdpi.com/2072-6643/12/11/3273

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

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Cannabinoid Receptor Subtype 2 (CB2R) in a Multitarget Approach: Perspective of an Innovative Strategy in Cancer and Neurodegeneration

 Go to Volume 0, Issue 0“The cannabinoid receptor subtype 2 (CB2R) represents an interesting and new therapeutic target for its involvement in the first steps of neurodegeneration as well as in cancer onset and progression.

Several studies, focused on different types of tumors, report a promising anticancer activity induced by CB2R agonists due to their ability to reduce inflammation and cell proliferation. Moreover, in neuroinflammation, the stimulation of CB2R, overexpressed in microglial cells, exerts beneficial effects in neurodegenerative disorders.

With the aim to overcome current treatment limitations, new drugs can be developed by specifically modulating, together with CB2R, other targets involved in such multifactorial disorders.

Building on successful case studies of already developed multitarget strategies involving CB2R, in this Perspective we aim at prompting the scientific community to consider new promising target associations involving HDACs (histone deacetylases) and σ receptors by employing modern approaches based on molecular hybridization, computational polypharmacology, and machine learning algorithms.”

https://pubmed.ncbi.nlm.nih.gov/33094613/

https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01357

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The Activation of Cannabinoid Type-2 Receptor with JWH-133 Protects Uterine Ischemia/Reperfusion-Induced Damage

 Pharmacology - Home - Karger Publishers“Uterus transplantation is a complex surgical procedure. Uterine ischemia/reperfusion (IR) damage occurring in this process may cause loss of function in the uterus. Cell damage must be prevented for a healthy uterine function and successful transplantation.

Cannabinoids, with their increasing clinical use, are substances with strong anti-inflammatory and antioxidative effects and have a role in immune system regulation. However, their efficacy in uterine IR damage is still unknown.

This study provides information on the potential applications cannabinoids agonist JWH-133 in uterine IR damage and, hence, in the transplant process.

Results: In the uterine IR group, NF-κB expression and MDA levels were detected at high levels. Histopathological examinations and TUNEL staining revealed extensive cell damage. On the other hand, in groups treated with JWH-133, dose-dependent NF-κB expression and MDA levels decreased (p < 0.05). Depending on the dose, the rate of surviving cells increased in TUNEL staining results.

Conclusion: The results showed that JWH-133 was effective in reducing uterine IR damage. Cannabinoids may be a new alternative that may be used in the transplantation process in the future.”

https://pubmed.ncbi.nlm.nih.gov/33105141/

https://www.karger.com/Article/Abstract/511457

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Signaling Through the Type 2 Cannabinoid Receptor Regulates the Severity of Acute and Chronic Graft versus Host Disease

Blood“Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments.

In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2R-EGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions.

Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH-133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase.

These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.”

https://pubmed.ncbi.nlm.nih.gov/33027805/

https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2020004871/464166/Signaling-Through-the-Type-2-Cannabinoid-Receptor?redirectedFrom=fulltext

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The impact of cannabinoid type 2 receptors (CB2Rs) in neuroprotection against neurological disorders

 Acta Pharmacologica Sinica“Cannabinoids have long been used for their psychotropic and possible medical properties of symptom relief. In the past few years, a vast literature shows that cannabinoids are neuroprotective under different pathological situations.

Most of the effects of cannabinoids are mediated by the well-characterized cannabinoid receptors, the cannabinoid type 1 receptor (CB1R) and cannabinoid type 2 receptor (CB2R). Even though CB1Rs are highly expressed in the central nervous system (CNS), the adverse central side effects and the development of tolerance resulting from CB1R activation may ultimately limit the clinical utility of CB1R agonists. In contrast to the ubiquitous presence of CB1Rs, CB2Rs are less commonly expressed in the healthy CNS but highly upregulated in glial cells under neuropathological conditions.

Experimental studies have provided robust evidence that CB2Rs seem to be involved in the modulation of different neurological disorders. In this paper, we summarize the current knowledge regarding the protective effects of CB2R activation against the development of neurological diseases and provide a perspective on the future of this field. A better understanding of the fundamental pharmacology of CB2R activation is essential for the development of clinical applications and the design of novel therapeutic strategies.”

https://pubmed.ncbi.nlm.nih.gov/33024239/

https://www.nature.com/articles/s41401-020-00530-2

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