Category Archives: Endocannabinoid System

Cannabinoid receptor 2 promotes the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.

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International Immunopharmacology“High mobility group box 1 (HMGB1) is a late phase inflammatory mediator in many inflammatory diseases. Extracellular HMGB1 could bind to many membrane receptors to activate downstream signaling molecules and promote inflammation resulting in cell and tissue damage.

In our previous work, we found cannabinoid receptor Ⅱ(CB2R) inhibited the expression of HMGB1 in lipopolysaccharide (LPS)-induced septic models in vivo and in vitro, but the underlying mechanism is still unclear.

The present study was aimed to explore the possible pathway through which CB2R suppressed HMGB1.

Here, we found that the specific agonist of CB2R, GW405833 (GW) could induce intracellular HMGB1 degradation without influencing HMGB1 mRNA in peritoneal macrophages. Then we observed that autophagy inhibitor 3-methyladenine (3-MA) but not proteasome inhibitor MG-132 (MG) could block GW-induced HMGB1 degradation, which indicated that the autophagy-lysosome but not the ubiquitination pathway was involved in this process.

Further study showed that GW could promote the integrity of autophagy flux in macrophages in terms of increased level of LC3Ⅱand decreased expression of p62 protein. It also observed that inhibition of autophagy blocked GW-induced nuclear translocation of HMGB1 in macrophages. GW could up-regulate expression of Cathepsin B (CTSB), and inhibition of CTSB blocked GW-induced HMGB1 degradation.

In summary, all the data showed that activation of CB2R could promote the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.”

https://www.ncbi.nlm.nih.gov/pubmed/31806570

https://www.sciencedirect.com/science/article/pii/S1567576919321186?via%3Dihub

Cannabinoids and the Microbiota-Gut-Brain-Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders.

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Alcoholism: Clinical and Experimental Research banner“The endocannabinoid system (ECS) has emerged in recent years as a potential treatment target for alcohol use disorders (AUD).

In particular, the non-psychoactive cannabinoid cannabidiol (CBD) has shown preclinical promise in ameliorating numerous clinical symptoms of AUD.

There are several proposed mechanism(s) through which cannabinoids (and CBD in particular) may confer beneficial effects in the context of AUD. First, CBD may directly impact specific brain mechanisms underlying AUD to influence alcohol consumption and the clinical features of AUD. Second, CBD may influence AUD symptoms through its actions across the digestive, immune, and central nervous systems, collectively known as the microbiota-gut-brain-axis (MGBA).

Notably, emerging work suggests that alcohol and cannabinoids exert opposing effects on the MGBA.

Alcohol is linked to immune dysfunction (e.g., chronic systemic inflammation in the brain and periphery) as well as disturbances in gut microbial species (microbiota) and increased intestinal permeability. These MGBA disruptions have been associated with AUD symptoms such as craving and impaired cognitive control.

Conversely, existing preclinical data suggest that cannabinoids may confer beneficial effects on the gastrointestinal and immune system, such as reducing intestinal permeability, regulating gut bacteria and reducing inflammation. Thus, cannabinoids may exert AUD harm-reduction effects, at least in part, through their beneficial actions across the MGBA.

This review will provide a brief introduction to the ECS and the MGBA, discuss the effects of cannabinoids (particularly CBD) and alcohol in the brain, gut, and immune system (i.e., across the MGBA), and put forth a theoretical framework to inform future research questions.”

https://www.ncbi.nlm.nih.gov/pubmed/31803950

https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.14256

Cannabinoids: A Guide for Use in the World of Gastrointestinal Disease.

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Image result for ovid journal“Cannabinoids have been known as the primary component of cannabis for decades, but the characterization of the endocannabinoid system (ECS) in the 1990s opened the doors for cannabis’ use in modern medicine.

The 2 main receptors of this system, cannabinoid receptors 1 and 2, are found on cells of various tissues, with significant expression in the gastrointestinal (GI) tract. The characterization of the ECS also heralded the understanding of endocannabinoids, naturally occurring compounds synthesized in the human body.

Although research on the effects of both endogenous and exogenous cannabinoids has been slow due to the complicated legal history of cannabis, discoveries of cannabinoids‘ treatment potential have been found in various fields of medicine, including the GI world.

Medical cannabis has since been offered as a treatment for a myriad of conditions and malignancies, including cancer, human immunodeficiency virus/acquired immunodeficiency syndrome, multiple sclerosis, chronic pain, nausea, posttraumatic stress disorder, amyotrophic lateral sclerosis, cachexia, glaucoma, and epilepsy.

This article hopes to create an overview of current research on cannabinoids and the ECS, detail the potential advantages and pitfalls of their use in GI diseases, and explore possible future developments in this field.”

https://www.ncbi.nlm.nih.gov/pubmed/31789770

https://insights.ovid.com/crossref?an=00004836-900000000-97668

The role of the endocannabinoid system in aetiopathogenesis of endometriosis: A potential therapeutic target.

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European Journal of Obstetrics and Gynecology Home“Endometriosis affects a large proportion of women during their reproductive years and is associated with pain and infertility, also affecting psychological wellbeing and quality of life. The pathogenesis of the disease remains unclear, although it is believed to be multifactorial.

The endocannabinoid system (ECS) consists of a number of ligands, receptors and enzymes, and has gained interests in endometriosis research. This review aims to summarise all available evidence reporting the roles of the ECS in endometriosis.

A literature search of the PubMed, EMBASE, and Web of Science electronic medical databases was performed. Original and review articles published in peer-reviewed journals were included. No publication date or publication status restrictions were imposed.

Significant differences in the concentrations and expressions of the components of the ECS were reported in the eutopic and ectopic endometrium, and the systemic circulation of women with endometriosis compared to controls. Endometriosis appears to be associated with downregulation of CB1 receptors and upregulation of TRPV1 receptors.

The role of CB1 and progesterone in anti-inflammatory action and the role of TRPV1 in inflammation and pain are of particular interests. Furthermore, the ECS has been reported to be involved in processes relevant to endometriosis, including cell migration, cell proliferation, apoptosis, inflammation, and interacts with sex steroid hormones.

The ECS may play a role in disease establishment, progression, and pain in endometriosis. However, reports are based on studies of limited size and there are inconsistencies among the definition of their control groups. There are also conflicting reports regarding precise involvement of the ECS in endometriosis. Future research with larger numbers, strict inclusion and exclusion criteria and detailed clinical information is imperative.”

https://www.ncbi.nlm.nih.gov/pubmed/31785471

https://www.ejog.org/article/S0301-2115(19)30526-3/fulltext

Investigation of the Involvement of the Endocannabinoid System in TENS-induced Antinociception.

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“Transcutaneous electrical nerve stimulation (TENS) promotes antinociception by activating the descending pain modulation pathway and consequently releasing endogenous analgesic substances.

In addition, recent studies have shown that the endocannabinoid system controls pain. Thus, the present study investigated the involvement of the endocannabinoid system in TENS-induced antinociception of cancer pain using a cancer pain model induced by intraplantar (i.pl.) injections of Ehrlich tumor cells in male Swiss mice.

These results suggest that low- and high-frequency TENS is effective in controlling cancer pain, and the endocannabinoid system is involved in this effect at both the peripheral and central levels.

Perspective: TENS is a non-pharmacological strategy that may be used to control cancer pain. Identification of a new mechanism involved in its analgesic effect could lead to the development of clinical studies as well as an increase in its application, lessening the need for pharmacological treatments.”

https://www.ncbi.nlm.nih.gov/pubmed/31785404

https://www.jpain.org/article/S1526-5900(19)30868-5/fulltext

Influence of the CB1 and CB2 cannabinoid receptor ligands on the activity of atypical antidepressant drugs in the behavioural tests in mice.

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Pharmacology Biochemistry and Behavior“Available data support the notion that cannabinoids, whose therapeutic value is limited due to severe adverse reactions, could be beneficial as adjunctive agents in the management of mood disorders.

Polytherapy, which is superior to monotherapy in the terms of effectiveness, usually requires lower doses of the individual components. Therefore, the main objective of our study was to determine whether administration of cannabinoid (CB) receptor ligands would enhance the antidepressant activity of atypical antidepressant drugs, i.e. agomelatine and tianeptine.

In summary, the outcomes of the present study showed that activation and inhibition of CB1 receptors as well as inhibition of CB2 receptors may increase the antidepressant activity of tianeptine, whereas only inhibition of CB1 and CB2 receptors has a potential to augment the antidepressant activity of agomelatine.”

https://www.ncbi.nlm.nih.gov/pubmed/31785246

https://www.sciencedirect.com/science/article/pii/S0091305719304873?via%3Dihub

The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases.

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 ijms-logo“Endocannabinoid system consists of cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors, their endogenous ligands, and the enzymes responsible for their synthesis and degradation. CB2, to a great extent, and CB1, to a lesser extent, are involved in regulating the immune response. They also regulate the inflammatory processes by inhibiting pro-inflammatory mediator release and immune cell proliferation. This review provides an overview on the role of the endocannabinoid system with a major focus on cannabinoid receptors in the pathogenesis and onset of inflammatory and autoimmune pediatric diseases, such as immune thrombocytopenia, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, obesity, neuroinflammatory diseases, and type 1 diabetes mellitus. These disorders have a high social impact and represent a burden for the healthcare system, hence the importance of individuating more innovative and effective treatments. The endocannabinoid system could address this need, representing a possible new diagnostic marker and therapeutic target.”

https://www.ncbi.nlm.nih.gov/pubmed/31771129

https://www.mdpi.com/1422-0067/20/23/5875

The curative effect of a cannabinoid 2 receptor agonist on functional failure and disruptive inflammation caused by intestinal ischemia and reperfusion.

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Publication cover image“As we learn more about the endocannabinoid system (ECS), our understanding and grasp of the system’s ubiquitous presence is expanding. In light of this, there is also a growing body of evidence for the therapeutic potential of ECS modulation in a range of clinical situations. Strategies include for example manipulation of the Cannabinoid 1 (CB1) receptor, mostly in terms of CNS processes, and activation of the Cannabinoid 2 (CB2) receptor as anti-inflammatory target.”

https://www.ncbi.nlm.nih.gov/pubmed/31774568

https://onlinelibrary.wiley.com/doi/abs/10.1111/fcp.12524

Alcohol Binge-Induced Cardiovascular Dysfunction Involves Endocannabinoid-CB1-R Signaling.

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 JACC: Basic to Translational Science“Excessive binge alcohol drinking may adversely affect cardiovascular function. In this study we characterize the detailed hemodynamic effects of an acute alcohol binge in mice using multiple approaches and investigate the role of the endocannabinoid-cannabinoid 1 receptor (CB1-R) signaling in these effects. Acute alcohol binge was associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction lasting for several hours and redistribution of circulation. These changes were attenuated by CB1-R antagonist or in CB1-R knockout mice. Our results suggest that a single alcohol binge has profound effects on the cardiovascular system, which involve endocannabinoid-CB1-R signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/31768478

“Alcohol is one of the most frequently used intoxicants in the United States. Binge alcohol drinking is a major contributor of emergency department visits. Binge alcohol drinking may adversely affect cardiovascular function. Here we show that acute alcohol intoxication is associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction and blood redistribution lasting for several hours. The adverse cardiovascular effects of acute alcohol intoxication are attenuated by CB1-R antagonist or in CB1-R knockout mice. A single alcohol binge has profound effect on the cardiovascular system, which involves endocannabinoid-CB1-R signaling.”

https://www.sciencedirect.com/science/article/pii/S2452302X19301755?via%3Dihub

Cannabinoid-2 receptor activation ameliorates hepatorenal syndrome.

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Free Radical Biology and Medicine“Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease characterized by the rapid decline of kidney function. Herein, we explored the therapeutic potential of targeting the cannabinoid 2 receptor (CB2-R) utilizing a commonly used mouse model of liver fibrosis and hepatorenal syndrome (HRS), induced by bile duct ligation (BDL).

KEY RESULTS:

We found that liver injury triggered marked inflammation and oxidative stress also in the kidneys of BDL-operated mice. We detected pronounced histopathological alterations with tubular injury paralleled with increased inflammation, oxidative/nitrative stress and fibrotic remodeling both in hepatic and renal tissues as well as endothelial activation and markedly impaired renal microcirculation. This was accompanied by increased CB2-R expression in both liver and the kidney tissues of diseased animals. A selective CB2-R agonist, HU-910, markedly decreased numerous markers of inflammation, oxidative stress and fibrosis both in the liver and in the kidneys. HU-910 also attenuated markers of kidney injury and improved the impaired renal microcirculation in BDL-operated mice.

CONCLUSIONS:

Our results suggest that oxidative stress, inflammation and microvascular dysfunction are key events in the pathogenesis of BDL-associated renal failure. Furthermore, we demonstrate that targeting the CB2-R by selective agonists may represent a promising new avenue to treat HRS by attenuating tissue and vascular inflammation, oxidative stress, fibrosis and consequent microcirculatory dysfunction in the kidneys.”

https://www.ncbi.nlm.nih.gov/pubmed/31770583

“Bile duct ligation (BDL) causes hepatorenal syndrome (HRS). Oxidative damage/inflammation drives liver and kidney injury following BDL. Cannabinoid-2 receptor (CB2-R) activation attenuates hepatic damage in BDL. CB2-R activation mitigates the renal inflammation and oxidative damage in BDL. CB2-R activation attenuates renal microcirculatory dysfunction in BDL.”

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