Category Archives: Endocannabinoid System

Systematic review of the impact of cannabinoids on neurobehavioral outcomes in preclinical models of traumatic and nontraumatic spinal cord injury

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Spinal Cord“Objectives: To evaluate the impact of cannabinoids on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI), with the aim of determining suitability for clinical trials involving SCI patients.

Results: The search returned 8714 studies, 19 of which met our inclusion criteria. Sample sizes ranged from 23 to 390 animals. WIN 55,212-2 (n = 6) and AM 630 (n = 8) were the most used cannabinoid receptor agonist and antagonist respectively. Acute SCI models included traumatic injury (n = 16), ischaemia/reperfusion injury (n = 2), spinal cord cryoinjury (n = 1) and spinal cord ischaemia (n = 1). Assessment tools used assessed locomotor function, pain and anxiety. Cannabinoid receptor agonists resulted in statistically significant improvement in locomotor function in 9 out of 10 studies and pain outcomes in 6 out of 6 studies.

Conclusion: Modulation of the endo-cannabinoid system has demonstrated significant improvement in both pain and locomotor function in pre-clinical SCI models; however, the risk of bias is unclear in all studies. These results may help to contextualise future translational clinical trials investigating whether cannabinoids can improve pain and locomotor function in SCI patients.”

https://pubmed.ncbi.nlm.nih.gov/34392312/

“The results of these studies demonstrate that modulation of the endo-cannabinoid system has significant benefit for both pain and locomotor function across a range of pre-clinical models of acute spinal cord injury.”

https://www.nature.com/articles/s41393-021-00680-y

Localisation of Cannabinoid and Cannabinoid-Related Receptors in the Horse Ileum

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Journal of Equine Veterinary Science“Colic is a common digestive disorder in horses and one of the most urgent problems in equine medicine. A growing body of literature has indicated that the activation of cannabinoid receptors could exert beneficial effects on gastrointestinal inflammation and visceral hypersensitivity.

The localisation of cannabinoid and cannabinoid-related receptors in the intestine of the horse has not yet been investigated. The purpose of this study was to immunohistochemically localise the cellular distribution of canonical and putative cannabinoid receptors in the ileum of healthy horses.

Distal ileum specimens were collected from six horses at the slaughterhouse. The tissues were fixed and processed to obtain cryosections which were used to investigate the immunoreactivity of canonical cannabinoid receptors 1 (CB1R) and 2 (CB2R), and three putative cannabinoid-related receptors: nuclear peroxisome proliferator-activated receptor-alpha (PPARα), transient receptor potential ankyrin 1 and serotonin 5-HT1a receptor (5-HT1aR).

Cannabinoid and cannabinoid-related receptors showed a wide distribution in the ileum of the horse.

The epithelial cells showed immunoreactivity for CB1R, CB2R and 5-HT1aR. Lamina propria inflammatory cells showed immunoreactivity for CB2R and 5-HT1aR. The enteric neurons showed immunoreactivity for CB1R, transient receptor potential ankyrin 1 and PPARα. The enteric glial cells showed immunoreactivity for CB1R and PPARα. The smooth muscle cells of the tunica muscularis and the blood vessels showed immunoreactivity for PPARα.

The present study represents a histological basis which could support additional studies regarding the distribution of cannabinoid receptors during gastrointestinal inflammatory diseases as well as studies assessing the effects of non-psychotic cannabis-derived molecules in horses for the management of intestinal diseases.”

https://pubmed.ncbi.nlm.nih.gov/34416995/

“Horses are often affected by gastrointestinal pathologies. Researchers are searching for new therapies for equine gastrointestinal diseases. New products with cannabinoid receptor agonists have been produced for horses. Cannabinoid receptors showed a wide distribution in the ileum of the horse. Activation of cannabinoids receptors could attenuate intestinal inflammation.”

https://www.sciencedirect.com/science/article/abs/pii/S073708062100318X?via%3Dihub

 

The Impact of CB1 Receptor on Inflammation in Skeletal Muscle Cells

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Dove Medical Press - Open Access Publisher of Medical Journals“Background: Various factors trigger the inflammatory response and cytokine activation in skeletal muscle. Inflamed muscle will exhibit significant levels of inflammation and cytokine activity. Interleukin-6 (IL-6), a pro-inflammatory cytokine, exerts pleiotropic effects on skeletal muscle. Endocannabinoid produced by all cell types binds to a class of G protein-coupled receptors, in particular cannabinoid CB1 receptors, to induce skeletal muscle actions.

Objective: The purpose of this research was to discover whether activation of cannabinoid CB1 receptors in L6 skeletal muscle cells may promote IL-6 gene expression.

Materials and methods: L6 skeletal muscle cells were cultured in 25 cm2 flasks and quantitative reverse transcription-polymerase chain reaction (probe-based) utilised to quantify IL-6 gene expression levels among different treatment settings.

Results: Arachidonyl-2′-chloroethylamide (ACEA) 10 nM, a persistent selective CB1 receptor agonist, promotes IL-6 gene expression in a time-dependent manner. Rimonabant 100 nM, a selective cannabinoid CB1 receptor antagonist, blocks the impact of ACEA. However, insulin does not change IL-6 gene expression.

Conclusion: For the first time, a unique link between ACEA and IL-6 up-regulation has been established; IL-6 up-regulation generated by ACEA is mediated in skeletal muscle through cannabinoid CB1 receptor activation. As a result, cannabinoid CB1 receptors may be useful pharmaceutical targets in the treatment of inflammation and related disorders in skeletal muscle tissues.”

https://pubmed.ncbi.nlm.nih.gov/34421307/

“In the present study, I have demonstrated that when cannabinoid CB1 receptors are activated, the expression of IL-6 increases in a way that is influenced by time. Such findings deliver a novel mechanism characterised by cannabinoid analogue playing the role of a pro-inflammatory mediator in the skeletal muscle tissue. The findings from the present study also imply that there may be a possible therapeutic use of cannabinoid CB1 receptor antagonist at acute early states for skeletal muscle dysfunction related to inflammation. My findings point to skeletal muscle cell cannabinoid CB1 receptor as a therapeutic target, and expand its potential to include anti-inflammatory effects in diabetes, obesity, and sarcopenia.”

https://www.dovepress.com/the-impact-of-cb1-receptor-on-inflammation-in-skeletal-muscle-cells-peer-reviewed-fulltext-article-JIR

Pharmacological characterisation of the CB 1 receptor antagonist activity of cannabidiol in the rat vas deferens bioassay

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European Journal of Pharmacology“Cannabidiol is increasingly considered for treatment of a wide range of medical conditions. Binding studies suggest that cannabidiol binds to CB1 receptors. In the rat isolated vas deferens bioassay, a single electrical pulse causes a biphasic contraction from nerve-released ATP and noradrenaline. WIN 55,212-2 acts on prejunctional CB1 receptors to inhibit release of these transmitters. In this bioassay, we tested whether cannabidiol and SR141716 were acting as competitive antagonists of this receptor. Monophasic contractions mediated by ATP or noradrenaline in the presence of prazosin or NF449 (P2X1 inhibitor), respectively, were measured to a single electrical pulse delivered every 30 min. Following treatment with cannabidiol (10-100 μM) or SR141716 (0.003-10 μM), cumulative concentrations of WIN 55,212-2 (0.001-30 μM) were applied followed by a single electrical pulse. The WIN 55,212-2 concentration-contraction curve EC50 values were applied to global regression analysis to determine the pKB. The antagonist potency of cannabidiol at the CB1 receptor in the rat vas deferens bioassay matched the reported receptor binding affinity. Cannabidiol was a competitive antagonist of WIN 55,212-2 with pKB values of 5.90 when ATP was the effector transmitter and 5.29 when it was noradrenaline. Similarly, SR141716 was a competitive antagonist with pKB values of 8.39 for ATP and 7.67 for noradrenaline as the active transmitter. Cannabidiol’s low micromolar CB1 antagonist pKB values suggest that at clinical blood levels (1-3 μM) it may act as a CB1 antagonist at prejunctional neuronal sites with more potency when ATP is the effector than for noradrenaline.”

https://pubmed.ncbi.nlm.nih.gov/34416240/

https://www.sciencedirect.com/science/article/abs/pii/S0014299921005860?via%3Dihub

In quest of a new therapeutic approach in COVID-19: the endocannabinoid system

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Publication Cover“The SARS-Cov-2 virus caused a high morbidity and mortality rate disease, that is the COVID-19 pandemic. Despite the unprecedented research interest in this field, the lack of specific treatments leads to severe complications in a high number of cases.

Current treatment includes antivirals, corticosteroids, immunoglobulins, antimalarials, interleukin-6 inhibitors, anti-GM-CSF, convalescent plasma, immunotherapy, antibiotics, circulation support, oxygen therapy, and circulation support. Due to the limited results, until specific treatments are available, other therapeutic approaches need to be considered.

The endocannabinoid system is found in multiple systems within the human body, including the immune system. Its activation can lead to beneficial results such as decreased viral entry, decreased viral replication, and a decrease in pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α, or IFN-γ. Moreover, endocannabinoid system activation can lead to an increase in anti-inflammatory cytokines, mainly represented by IL-10.

Overall, the cannabinoid system can potentially reduce pulmonary inflammation, increase the immunomodulatory effect, decrease PMN infiltration, reduce fibrosis, and decrease viral replication, as well as decrease the ‘cytokine storm’. Although the cannabinoid system has many mechanisms to provide certain benefits in the treatment of SARS-CoV-2 infected patients, research in this field is needed for a better understanding of the cannabinoid impact in this situation.”

https://pubmed.ncbi.nlm.nih.gov/33683968/

“Concerning the SARS-CoV-2 infection, the cannabinoid effects on the immune system have the potential to limit the abnormal function of the immune system and therefore decrease the overall mortality.”

https://www.tandfonline.com/doi/full/10.1080/03602532.2021.1895204

Cannabinoids for skin diseases and hair regrowth

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“The use of cannabis for skin diseases and hair regrowth is at the preliminary stage.

Legalization: Many countries have approved cannabis for medical use; however, four countries Canada, Uruguay, South Africa, and Georgia have legalized it for both medical and recreational purposes.

The endocannabinoid system: The endocannabinoid system may maintain skin homeostasis; two notable endocannabinoids include 2-Arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA).

Routes of administration and pharmacokinetics: Topical cannabinoids can avoid the first-pass metabolism and reduce respiratory side effects; however, the high hydrophobicity of cannabinoids may hinder percutaneous absorption.

Skin disorders and hair growth: Human clinical studies suggest that cannabinoids may be used in eczema, acne, pruritus, and systemic sclerosis treatment. Cannabidiol (CBD) may enhance hair growth via multiple mechanisms.

Safety: Topical cannabis may cause mild side effects such as pruritus, burning, erythema, and stinging; they are relatively safer than inhalation and oral cannabis. Cannabis use may be associated with allergic symptoms and reduced immune response to live vaccination.

Cannabinoids in practice: Despite growing interest, dermatologists should be cautious prescribing cannabinoids due to insufficient clinical data on both efficacy and safety.”

https://pubmed.ncbi.nlm.nih.gov/34363728/

https://onlinelibrary.wiley.com/doi/10.1111/jocd.14352

 

An overview on plants cannabinoids endorsed with cardiovascular effects

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Biomedicine & Pharmacotherapy“Nowadays cardiovascular diseases (CVDs) are the major causes for the reduction of the quality of life.

The endocannabinoid system is an attractive therapeutic target for the treatment of cardiovascular disorders due to its involvement in vasomotor control, cardiac contractility, blood pressure and vascular inflammation. Alteration in cannabinoid signalling can be often related to cardiotoxicity, circulatory shock, hypertension, and atherosclerosis.

Plants have been the major sources of medicines until modern eras in which researchers are experiencing a rediscovery of natural compounds as novel therapeutics.

One of the most versatile plant is Cannabis sativa L., containing phytocannabinoids that may play a role in the treatment of CVDs.

The aim of this review is to collect and investigate several less studied plants rich in cannabinoid-like active compounds able to interact with cannabinoid system; these plants may play a pivotal role in the treatment of disorders related to the cardiovascular system.”

https://pubmed.ncbi.nlm.nih.gov/34332376/

“Cannabis sativa L. is the most investigated source of phytocannabinoids. Other plants are a rich source of cannabinoid-like compounds. Cannabinoid-like compounds may interact with cannabinoid system. Most of them may exhibit a protective role on cardiovascular system.” 

https://www.sciencedirect.com/science/article/pii/S0753332221007459?via%3Dihub

 

Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

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molecules-logo“In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite.

The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion.

The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers.

The therapeutic potential of cannabinoids for cancer-both in vivo and in vitro clinical trials-has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers.

In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.”

https://pubmed.ncbi.nlm.nih.gov/34205169/

https://www.mdpi.com/1420-3049/26/11/3389

Epigenetic Regulation of Cannabinoid-Mediated Attenuation of Inflammation and Its Impact on the Use of Cannabinoids to Treat Autoimmune Diseases

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ijms-logo“Chronic inflammation is considered to be a silent killer because it is the underlying cause of a wide range of clinical disorders, from cardiovascular to neurological diseases, and from cancer to obesity. In addition, there are over 80 different types of debilitating autoimmune diseases for which there are no cure. Currently, the drugs that are available to suppress chronic inflammation are either ineffective or overtly suppress the inflammation, thereby causing increased susceptibility to infections and cancer. Thus, the development of a new class of drugs that can suppress chronic inflammation is imperative.

Cannabinoids are a group of compounds produced in the body (endocannabinoids) or found in cannabis (phytocannabinoids) that act through cannabinoid receptors and various other receptors expressed widely in the brain and immune system. In the last decade, cannabinoids have been well established experimentally to mediate anti-inflammatory properties. Research has shown that they suppress inflammation through multiple pathways, including apoptosis and inducing immunosuppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs).

Interestingly, cannabinoids also mediate epigenetic alterations in genes that regulate inflammation. In the current review, we highlight how the epigenetic modulations caused by cannabinoids lead to the suppression of inflammation and help identify novel pathways that can be used to target autoimmune diseases.”

https://pubmed.ncbi.nlm.nih.gov/34298921/

https://www.mdpi.com/1422-0067/22/14/7302

Pros and Cons of the Cannabinoid System in Cancer: Focus on Hematological Malignancies

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molecules-logo“The endocannabinoid system (ECS) is a composite cell-signaling system that allows endogenous cannabinoid ligands to control cell functions through the interaction with cannabinoid receptors. Modifications of the ECS might contribute to the pathogenesis of different diseases, including cancers. However, the use of these compounds as antitumor agents remains debatable.

Pre-clinical experimental studies have shown that cannabinoids (CBs) might be effective for the treatment of hematological malignancies, such as leukemia and lymphoma.

Specifically, CBs may activate programmed cell death mechanisms, thus blocking cancer cell growth, and may modulate both autophagy and angiogenesis. Therefore, CBs may have significant anti-tumor effects in hematologic diseases and may synergistically act with chemotherapeutic agents, possibly also reducing chemoresistance.

Moreover, targeting ECS might be considered as a novel approach for the management of graft versus host disease, thus reducing some symptoms such as anorexia, cachexia, fatigue, anxiety, depression, and neuropathic pain. The aim of the present review is to collect the state of the art of CBs effects on hematological tumors, thus focusing on the essential topics that might be useful before moving into the clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/34202812/

https://www.mdpi.com/1420-3049/26/13/3866