The Impact of Cannabinoid Receptor 2 Deficiency on Neutrophil Recruitment and Inflammation.

View details for DNA and Cell Biology cover image“Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines.

A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB2) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury.

Recent work in preclinical models of inflammation raises two questions: by what mechanisms do CB2 agonists provide anti-inflammatory effects during acute inflammation and what challenges exist in the translation of CB2 modulating therapeutics into the clinic.”

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Interplay of liver-heart inflammatory axis and cannabinoid 2 receptor signalling in an experimental model of hepatic cardiomyopathy.

Publication cover image“Hepatic cardiomyopathy, a special type of heart failure develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable model of hepatic cardiomyopathy in mice. Herein we aimed to characterize the detailed hemodynamics of mice with bile-duct ligation (BDL)-induced liver fibrosis, by monitoring echocardiography and intracardiac pressure-volume (PV) relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid-2 receptor (CB2 -R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation, fibrosis on cardiac function.

MAIN RESULTS:

BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic and macrovascular functions, cardiac inflammation (increased MIP1, interleukin-1, P-selectin, CD45+ cells) and oxidative stress (increased malondialdehyde, 3-nitrotyrosine and NADPH-oxidases). CB2 -R up-regulation was observed both in livers and hearts of mice exposed to BDL. CB2 -R activation markedly improved hepatic inflammation, impaired microcirculation, fibrosis. CB2 -R activation also decreased serum TNF-alpha levels, and improved cardiac dysfunction, myocardial inflammation and oxidative stress underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy.

CONCLUSION:

We propose BDL-induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similarly to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension, impaired macro- and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver-heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g. with selective CB2-R agonists) may delay/prevent the development of cardiomyopathy in severe liver disease. ”

https://www.ncbi.nlm.nih.gov/pubmed/31469200

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30916

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Role of the endocannabinoidome in human and mouse atherosclerosis.

“The Endocannabinoid (eCB) system and its role in many physiological and pathological conditions is well described and accepted, and includes cardiovascular disorders. However, the eCB system has been expanded to an “-ome”; the endocannabinoidome (eCBome) that includes endocannabinoid-related mediators, their protein targets and metabolic enzymes, many of which significantly impact upon cardiometabolic health. These recent discoveries are here summarized with a special focus on their potential involvement in atherosclerosis. We described the role of classical components of the eCB system (eCBs, CB1 and CB2 receptors) and eCB-related lipids, their regulatory enzymes and molecular targets in atherosclerosis. Furthermore, since increasing evidence points to significant cross-talk between the eCBome and the gut microbiome and the gut microbiome and atherosclerosis, we explore the possibility that a gut microbiome – eCBome axis has potential implications in atherosclerosis.”

https://www.ncbi.nlm.nih.gov/pubmed/31448709

http://www.eurekaselect.com/174465/article

“Oral cannabinoid therapy reduces progression of atherosclerosis”  https://www.medscape.com/viewarticle/787468

“The active ingredient in marijuana that produces changes in brain messages appears to fight atherosclerosis — a hardening of the arteries.” https://www.webmd.com/heart-disease/news/20050406/marijuana-chemical-fights-hardened-arteries

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The protective mechanism of cannabidiol in cardiac injury: A systematic review of non-clinical studies.

“Cardiac disease is accounted as the leading cause of worldwide morbidity and mortality, mainly in association with induction of inflammation and oxidative stress. The disease is characterized by the overproduction of reactive oxygen and/or nitrogen species (ROS/RNS), and reduced antioxidant capacity.

Cannabidiol (CBD) is a non-psychoactive ingredient of marijuana that reported to be safe and well tolerated in patients. Due to its pleiotropic effect, CBD has been shown to exert cytoprotective effects. This study intended to clarify the mechanisms and the potential role of CBD regarding cardiac injuries treatment.

RESULTS:

Our findings obviously demonstrate that CBD has multi-functional protective assets to improve cardiac injuries; preliminary through scavenging of free radicals, and reduction of oxidative stress, apoptosis, and inflammation.

CONCLUSION:

CBD can protect against cardiac injuries, mainly through its anti-oxidant, anti-inflammatory, and anti-apoptotic effects on the basis of non-clinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31291873

http://www.eurekaselect.com/173374/article

“Cytoprotection is a process by which chemical compounds provide protection to cells against harmful agents.” https://en.wikipedia.org/wiki/Cytoprotection

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The Endocannabinoid System and its Modulation by Cannabidiol (CBD).

Image result for Altern Ther Health Med. “The endocannabinoid system (ECS) is an extensive endogenous signaling system with multiple elements, the number of which may be increasing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like Cannabidiol (CBD). Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others.”

https://www.ncbi.nlm.nih.gov/pubmed/31202198

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l-α-Lysophosphatidylinositol (LPI) aggravates myocardial ischemia/reperfusion injury via a GPR55/ROCK-dependent pathway.

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“The phospholipid l-α-lysophosphatidylinositol (LPI), an endogenous ligand for GPR55, is elevated in patients with acute coronary syndrome, and a GPR55 antagonist cannabidiol (CBD) reduces experimental ischemia/reperfusion (I/R) injury.”

https://www.ncbi.nlm.nih.gov/pubmed/31149342

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp2.487

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β-Caryophyllene, a natural bicyclic sesquiterpene attenuates doxorubicin-induced cardiotoxicity via activation of myocardial cannabinoid type-2 (CB2) receptors in rats.

Chemico-Biological Interactions

“The cannabinoid type 2 receptor (CB2) has recently emerged as an important therapeutic target for cancer as well as cardiovascular diseases. The CB2 receptor downregulation has been reported in solid tumors and cardiovascular diseases, therefore the CB2receptor activation has been considered as a viable strategy for chemotherapy as well as cardioprotection.

In chemotherapy, doxorubicin (DOX) is an important drug that continues to be the mainstay of chemotherapy in solid tumors, leukemia, and lymphoma. However, the use of DOX is often limited due to its lethal cardiotoxicity. Considering the role of CB2 receptors in cardiovascular diseases and cancer, the activation of CB2 receptors may protect against DOX-induced chronic cardiotoxicity in rats.

In the present study, we investigated the cardioprotective effect of a selective CB2 receptor agonist; β-Caryophyllene (BCP), a natural bicyclic sesquiterpene, against DOX-induced chronic cardiotoxicity in rats. AM630, a CB2 receptor antagonist was administered as a pharmacological challenge prior to BCP treatment to demonstrate CB2 receptor mediated cardioprotective mechanism of BCP. DOX (2.5 mg/kg) was injected intraperitoneally once a week for five weeks to induce chronic cardiotoxicity in rats.

BCP was also injected into rats six days a week for a total duration of five weeks. DOX induced a significant decline in cardiac function and oxidative stress evidenced by the depletion of antioxidant enzymes, glutathione, and increased lipid peroxidation. DOX also triggered activation of nuclear factor kappa B (NF-κB) and increased the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and expression of the inflammatory mediators (iNOS and COX-2) in the heart.

Furthermore, DOX also upregulated the expression of pro-apoptotic markers such as Bax, p53, cleaved PARP, active caspase-3 and downregulated anti-apoptotic marker Bcl-2 in the myocardium. BCP treatment exerted significant cardioprotective effect by salvaging the heart tissues, improving cardiac function, mitigating oxidative stress, inflammation, and apoptosis. The histological and ultrastructural studies also appear in line with our findings of biochemical and molecular parameters.

The CB2 receptor-mediated cardioprotective mechanism was further confirmed by the abrogation of the beneficial effects of BCP with prior administration of the CB2 receptor antagonist; AM630.

Our study revealed the novel mechanism of BCP in cardioprotection against DOX-induced chronic cardiotoxicity by the activation of CB2 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/30836069

https://www.sciencedirect.com/science/article/pii/S0009279718316284?via%3Dihub

“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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The effects of cannabinoids on the endocrine system.

“Cannabinoids are the derivatives of the cannabis plant, the most potent bioactive component of which is tetrahydrocannabinol (THC). The most commonly used drugs containing cannabinoids are marijuana, hashish, and hashish oil.

These compounds exert their effects via interaction with the cannabinoid receptors CB1 and CB2. Type 1 receptors (CB1) are localised mostly in the central nervous system and in the adipose tissue and many visceral organs, including most endocrine organs. Type 2 cannabinoid receptors (CB2) are positioned in the peripheral nervous system (peripheral nerve endings) and on the surface of the immune system cells.

Recently, more and more attention has been paid to the role that endogenous ligands play for these receptors, as well as to the role of the receptors themselves. So far, endogenous cannabinoids have been confirmed to participate in the regulation of food intake and energy homeostasis of the body, and have a significant impact on the endocrine system, including the activity of the pituitary gland, adrenal cortex, thyroid gland, pancreas, and gonads.

Interrelations between the endocannabinoid system and the activity of the endocrine system may be a therapeutic target for a number of drugs that have been proved effective in the treatment of infertility, obesity, diabetes, and even prevention of diseases associated with the cardiovascular system.”

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Associations between cannabis use and cardiometabolic risk factors: A longitudinal study of men.

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“This study tested longitudinal associations between cannabis use and cardiometabolic risk factors that underlie the development of cardiovascular diseases.

RESULTS:

Greater cannabis exposure was associated with relatively lower BMI (β=-0.31, p<.001), smaller WHR (β=-0.23, p=.002), better HDL (β=0.14, p=.036) and LDL cholesterol (β=-0.15, p=.026), lower triglycerides (β=-0.17, p=.009), lower fasting glucose (β=-0.15, p<.001) and HOMA-IR (β=-0.21, p=.003), lower systolic (β=-0.22, p<.001) and diastolic blood pressure (β=-0.15, p=.028), and fewer metabolic syndrome criteria (β=-0.27, p<.001). With exception of BMI, cannabis users’ mean levels on cardiometabolic risk factors were generally below clinical cutoffs for high risk. Most associations between cannabis use and cardiometabolic risk factors remained after adjusting for tobacco use, childhood SES, and childhood health. However, after adjusting for adult BMI, these associations were no longer apparent, and mediation tests suggested that cannabis users’ relatively lower BMI might explain their lower levels of risk on other cardiometabolic risk factors.

CONCLUSIONS:

Cannabis use is associated with lower BMI, and lower BMI is related to lower levels of risk on other cardiometabolic risk factors.”

https://www.ncbi.nlm.nih.gov/pubmed/30589665

https://insights.ovid.com/crossref?an=00006842-900000000-98666

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Selective Activation of Cannabinoid Receptor 2 Attenuates Myocardial Infarction via Suppressing NLRP3 Inflammasome.

“The administration of cannabinoid receptor 2 (CB2R) agonist has been reported to produce a cardioprotective effect against the pathogenesis and progression of myocardial infarction (MI).

Here in this study, we investigated the specific mechanism related to inflammatory suppression. JWH-133 was used for the activation of CB2R.

Taken together, we demonstrated for the first time the cardioprotective effect of CB2R agonist and its NLRP3 inflammasome-related mechanism in MI.”

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