Category Archives: Endocannabinoid System

Δ9‐TETRAHYDROCANNABINOLIC ACID ALLEVIATES COLLAGEN‐INDUCED ARTHRITIS: ROLE OF PPARγ AND CB1 RECEPTORS

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British Journal of Pharmacology “Δ9‐THCA‐A, the precursor of Δ9‐THC, is a non‐psychotropic phytocannabinoid that shows PPARγ agonistic activity. Herein, we investigated Δ9‐THCA ability to modulate classic cannabinoid receptors (CB1 and CB2) and evaluated its anti‐arthritis activity.

Experimental Approach

Cannabinoid receptors binding and intrinsic activity, as well as their downstream signaling were analyzed in vitro and in silico . The anti‐arthritis properties of Δ9‐THCA‐A were studied in human chondrocytes and in the murine model of collagen‐induced arthritis (CIA). Plasmatic disease biomarkers were identified by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) based on proteomic and ELISA assays.

Key Results

Functional and docking analyses showed that Δ9‐THCA‐A can act as an orthosteric CB1 agonist and also as a positive allosteric modulator in the presence of CP‐55,940. In addition, Δ9‐THCA‐A seemed to be an inverse agonist for CB2. In vivo experiments showed that Δ9‐THCA‐A reduced arthritis in CIA mice. Δ9‐THCA‐A prevented the infiltration of inflammatory cells; synovium hyperplasia and cartilage damage. Furthermore, Δ9‐THCA‐A inhibited the expression of inflammatory and catabolic genes on knee joints. The anti‐arthritic effect of Δ9‐THCA‐A was ablated by either SR141716 or T0070907. Analysis of plasmatic biomarkers as well as determination of cytokines and anti‐collagen antibodies confirmed that Δ9‐THCA‐A mediates its activity mainly through PPARγ and CB1 pathways.

Conclusion and Implications

Δ9‐THCA‐A modulates CB1 receptor through the orthosteric and allosteric binding sites. In addition, our studies document that Δ9‐THCA‐A exerts anti‐arthritis activity through CB1/PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as Rheumatoid Arthritis (RA).”

https://pubmed.ncbi.nlm.nih.gov/32510591/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15155

 British Pharmacological Society | Journals

High Expression of Cannabinoid Receptor 2 on Cytokine-Induced Killer Cells and Multiple Myeloma Cells

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ijms-logo“Multiple myeloma (MM) is characterized by aberrant bone marrow plasma cell (PC) proliferation and is one of the most common hematological malignancies. The potential effect of cannabinoids on the immune system and hematological malignancies has been poorly characterized.

Cannabidiol (CBD) may be used to treat various diseases. CBD is known to exert immunomodulatory effects through the activation of cannabinoid receptor 2 (CB2), which is expressed in high levels in the hematopoietic system.

Cytokine-induced killer (CIK) cells are a heterogeneous population of polyclonal T lymphocytes obtained via ex vivo sequential incubation of peripheral blood mononuclear cells (PBMCs) with interferon-γ (IFN-γ), anti CD3 monoclonal antibody, and IL-2. They are characterized by the expression of CD3+ and CD56+, which are surface markers common to T lymphocytes and natural killer (NK) cells. CIK cells are mainly used in hematological patients who suffer relapse after allogeneic transplantation.

Here, we investigated their antitumor effect in combination with pure cannabidiol in KMS-12 MM cells by lactate dehydrogenase LDH cytotoxicity assay, CCK-8 assay, and flow cytometry analysis. The surface and intracellular CB2 expressions on CIK cells and on KMS-12 and U-266 MM cell lines were also detected by flow cytometry.

Our findings confirm that the CB2 receptor is highly expressed on CIK cells as well as on MM cells. CBD was able to decrease the viability of tumor cells and can have a protective role for CIK cells. It also inhibits the cytotoxic activity of CIKs against MM at high concentrations, so in view of a clinical perspective, it has to be considered that the lower concentration of 1 µM can be used in combination with CIK cells. Further studies will be required to address the mechanism of CBD modulation of CIK cells in more detail.”

https://pubmed.ncbi.nlm.nih.gov/32471216/

https://www.mdpi.com/1422-0067/21/11/3800

Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?

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ijms-logo“In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.”

https://pubmed.ncbi.nlm.nih.gov/32471272/

https://www.mdpi.com/1422-0067/21/11/3809

Effects of Chronic Cannabidiol Treatment in the Rat Chronic Unpredictable Mild Stress Model of Depression

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biomolecules-logo“Several neuropharmacological actions of cannabidiol (CBD) due to the modulation of the endocannabinoid system as well as direct serotonergic and gamma-aminobutyric acidergic actions have recently been identified.

The current study aimed to reveal the effect of a long-term CBD treatment in the chronic unpredictable mild stress (CUMS) model of depression.

Adult male Wistar rats (n = 24) were exposed to various stressors on a daily basis in order to induce anhedonia and anxiety-like behaviors. CBD (10 mg/kg body weight) was administered by daily intraperitoneal injections for 28 days (n = 12). The effects of the treatment were assessed on body weight, sucrose preference, and exploratory and anxiety-related behavior in the open field (OF) and elevated plus maze (EPM) tests. Hair corticosterone was also assayed by liquid chromatography-mass spectrometry.

At the end of the experiment, CBD-treated rats showed a higher rate of body weight gain (5.94% vs. 0.67%) and sucrose preference compared to controls. A significant increase in vertical exploration and a trend of increase in distance traveled in the OF test were observed in the CBD-treated group compared to the vehicle-treated group. The EPM test did not reveal any differences between the groups. Hair corticosterone levels increased in the CBD-treated group, while they decreased in controls compared to baseline (+36.01% vs. -45.91%). In conclusion, CBD exerted a prohedonic effect in rats subjected to CUMS, demonstrated by the increased sucrose preference after three weeks of treatment.

The reversal of the effect of CUMS on hair corticosterone concentrations might also point toward an anxiolytic or antidepressant-like effect of CBD, but this needs further confirmation.”

https://pubmed.ncbi.nlm.nih.gov/32455953/

https://www.mdpi.com/2218-273X/10/5/801

The Cannabis Spread Throughout the Continents and Its Therapeutic Use in History

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“Historical relevance: Cannabis sativa L. (C. sativa) is a plant whose use as a therapeutic agent shares its origins with the first Far East’s human societies. Cannabis has been used not only for recreational purposes, but as a food to obtain textile fibers, to produce hemp paper, to treat many physical and mental disorders.

This review aims to provide a complete assessment of the deep knowledge of the cannabis psychoactive effects and medicinal properties in the course of history covering i.) the empirical use of the seeds and the inflorescences to treat many physical ailments by the ancient Oriental physicians ii.) the current use of cannabis as a therapeutic agent after the discovery of its key psychoactive constituent and the human endogenous endocannabinoid system.

Results and conclusion: Through a detailed analysis of the available resources about the origins of C. sativa we found that its use by ancient civilizations as a source of food and textile fibers dates back over 10,000 years, while its therapeutic applications have been improved over the centuries, from the ancient East medicine of the 2nd and 1st millennium B.C. to the more recent introduction in the Western world after the 1st century A.D. In the 20th and 21th centuries, Cannabis and its derivatives have been considered as a menace and banned throughout the world, but nowadays they are still the most widely consumed illicit drugs all over the world. Its legalization in some jurisdictions has been accompanied by new lines of research to investigate its possible applications for medical and therapeutic purposes.”

https://pubmed.ncbi.nlm.nih.gov/32433013/?from_term=cannabinoid&from_sort=date&from_size=200&from_pos=6

http://www.eurekaselect.com/182145/article

Targeting Cannabinoid Receptor 2 on Peripheral Leukocytes to Attenuate Inflammatory Mechanisms Implicated in HIV-Associated Neurocognitive Disorder.

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 SpringerLink“HIV infection affects an estimated 38 million people. Approximately 50% of HIV patients exhibit neurocognitive dysfunction termed HIV-Associated Neurocognitive Disorder (HAND). HAND is a consequence of chronic low-level neuroinflammation due to HIV entry into the brain. Initially, monocytes become activated in circulation and traffic to the brain. Monocytes, when activated, become susceptible to infection by HIV and can then carry the virus across the blood brain barrier. Once in the brain, activated monocytes secrete chemokines, which recruit virus-specific CD8+ T cells into the brain to further promote neuroinflammation. HAND is closely linked to systemic inflammation driven, in part, by HIV but is also due to persistent translocation of microorganisms across the GI tract. Persistent anti-viral responses in the GI tract compromise microbial barrier integrity. Indeed, HIV patients can exhibit remarkably high levels of activated (CD16+) monocytes in circulation.

Recent studies, including our own, show that HIV patients using medical marijuana exhibit lower levels of circulating CD16+ monocytes than non-cannabis using HIV patients. Cannabis is a known immune modulator, including anti-inflammatory properties, mediated, in part, by ∆9-tetrahydrocannabinol (THC), as well as less characterized minor cannabinoids, such as cannabidiol (CBD), terpenes and presumably other cannabis constituents. The immune modulating activity of THC is largely mediated through cannabinoid receptors (CB) 1 and 2, with CB1 also responsible for the psychotropic properties of cannabis.

Here we discuss the anti-inflammatory properties of cannabinoids in the context of HIV and propose CB2 as a putative therapeutic target for the treatment of neuroinflammation. Graphical Abstract HIV-associated neurocognitive disorder is a systemic inflammatory disease leading to activation of plasmacytoid dendritic cells, monocytes and T cells. Monocyte and CD8 T cell migration across the BBB and interaction with astrocytes promotes neurotoxic inflammatory mediators release. CB2 ligands are proposed as therapeutics capable of suppressing systemic and localized inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/32409991

https://link.springer.com/article/10.1007%2Fs11481-020-09918-7

Activation of CB1R Promotes Lipopolysaccharide-Induced IL-10 Secretion by Monocytic Myeloid-Derived Suppressive Cells and Reduces Acute Inflammation and Organ Injury.

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The Journal of Immunology: 204 (10)“Cannabis sativa and its principal components, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol, are increasingly being used to treat a variety of medical problems, including inflammatory conditions.

Although studies suggest that the endocannabinoid system has immunomodulatory properties, there remains a paucity of information on the effects of cannabinoids on immunity and on outcomes of infection and injury.

We investigated the effects and mechanism(s) of action of cannabinoid receptor agonists, including Δ9-THC, on inflammation and organ injury in endotoxemic mice.

Administration of Δ9-THC caused a dramatic early upregulation of plasma IL-10 levels, reduced plasma IL-6 and CCL-2 levels, led to better clinical status, and attenuated organ injury in endotoxemic mice. The anti-inflammatory effects of Δ9-THC in endotoxemic mice were reversed by a cannabinoid receptor type 1 (CB1R) inverse agonist (SR141716), and by clodronate-induced myeloid-cell depletion, but not by genetic invalidation or blockade of other putative Δ9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although Δ9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of Δ9-THC were preserved in splenectomized endotoxemic mice. Finally, using IL-10-GFP reporter mice, we showed that blood monocytic myeloid-derived suppressive cells mediate the Δ9-THC-induced early rise in circulating IL-10.

These results indicate that Δ9-THC potently induces IL-10, while reducing proinflammatory cytokines, chemokines, and related organ injury in endotoxemic mice via the activation of CB1R. These data have implications for acute and chronic conditions that are driven by dysregulated inflammation, such as sepsis, and raise the possibility that CB1R-signaling may constitute a novel target for inflammatory disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32385136

https://www.jimmunol.org/content/early/2020/05/07/jimmunol.2000213

Cannabidiol and Other Non-Psychoactive Cannabinoids for Prevention and Treatment of Gastrointestinal Disorders: Useful Nutraceuticals?

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ijms-logo“Cannabis sativa is an aromatic annual flowering plant with several botanical varieties, used for different purposes, like the production of fibers, the production of oil from the seeds, and especially for recreational or medical purposes.

Phytocannabinoids (terpenophenolic compounds derived from the plant), include the well-known psychoactive cannabinoid Δ9-tetrahydrocannabinol, and many non-psychoactive cannabinoids, like cannabidiol.

The endocannabinoid system (ECS) comprises of endocannabinoid ligands, enzymes for synthesis and degradation of such ligands, and receptors. This system is widely distributed in the gastrointestinal tract, where phytocannabinoids exert potent effects, particularly under pathological (i.e., inflammatory) conditions.

Herein, we will first look at the hemp plant as a possible source of new functional food ingredients and nutraceuticals that might be eventually useful to treat or even prevent gastrointestinal conditions.

Subsequently, we will briefly describe the ECS and the general pharmacology of phytocannabinoids. Finally, we will revise the available data showing that non-psychoactive phytocannabinoids, particularly cannabidiol, may be useful to treat different disorders and diseases of the gastrointestinal tract.

With the increasing interest in the development of functional foods for a healthy life, the non-psychoactive phytocannabinoids are hoped to find a place as nutraceuticals and food ingredients also for a healthy gastrointestinal tract function.”

https://www.ncbi.nlm.nih.gov/pubmed/32357565

https://www.mdpi.com/1422-0067/21/9/3067

Targeting the Endocannabinoid System in Borderline Personality Disorder.

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“Borderline Personality Disorder (BPD) is a chronic debilitating psychiatric disorder characterized mainly by emotional instability, chaotic interpersonal relationships, cognitive disturbance (e.g. dissociation and suicidal thoughts) and maladaptive behaviors. BPD has a high rate of comorbidity with other mental disorders and high burden on society.

In this review, we focus on two compromised brain regions in BPD – the hypothalamus and the corticolimbic system, emphasizing the involvement and potential contribution of the endocannabinoid system (ECS) to improvement in symptoms and coping.

The hypothalamus-regulated endocrine axes (hypothalamic pituitary – gonadal, thyroid & adrenal) have been found to be dysregulated in BPD. There is also substantial evidence for limbic system structural and functional changes in BPD, especially in amygdala and hippocampus, including cortical regions within the corticolimbic system.

Extensive expression of CB1 and CB2 receptors of the ECS has been found in limbic regions and the hypothalamus. This opens new windows of opportunity for treatment with cannabinoids such as cannabidiol (CBD) as no other pharmacological treatment has shown long-lasting improvement in the BPD population to date.

This review aims to show the potential role of the ECS in BPD patients through their most affected brain regions, the hypothalamus and the corticolimbic system. The literature reviewed does not allow for general indications of treatment with CBD in BPD. However, there is enough knowledge to indicate a treatment ratio of high level of CBD to low level of THC.

A randomized controlled trial investigating the efficacy of cannabinoid based treatments in BPD is warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/32351183

http://www.eurekaselect.com/181504/article

Sensitivity of the Fasciae to the Endocannabinoid System: Production of Hyaluronan-Rich Vesicles and Potential Peripheral Effects of Cannabinoids in Fascial Tissue.

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ijms-logo “The demonstrated expression of endocannabinoid receptors in myofascial tissue suggested the role of fascia as a source and modulator of pain.

Fibroblasts can modulate the production of the various components of the extracellular matrix, according to type of stimuli: physical, mechanical, hormonal, and pharmacological. In this work, fascial fibroblasts were isolated from small samples of human fascia lata of the thigh, collected from three volunteer patients (two men, one woman) during orthopedic surgery.

This text demonstrates for the first time that the agonist of cannabinoid receptor 2, HU-308, can lead to in vitro production of hyaluronan-rich vesicles only 3-4 h after treatment, being rapidly released into the extracellular environment. We demonstrated that these vesicles are rich in hyaluronan after Alcian blue and Toluidine blue stainings, immunocytochemistry, and transmission electron microscopy. In addition, incubation with the antagonist AM630 blocked vesicles production by cells, confirming that release of hyaluronan is a cannabinoid-mediated effect.

These results may show how fascial cells respond to the endocannabinoid system by regulating and remodeling the formation of the extracellular matrix. This is a first step in our understanding of how therapeutic applications of cannabinoids to treat pain may also have a peripheral effect, altering the biosynthesis of the extracellular matrix in fasciae and, consequently, remodeling the tissue and its properties.”

https://www.ncbi.nlm.nih.gov/pubmed/32331297

https://www.mdpi.com/1422-0067/21/8/2936