Tag Archives: CB(1) and CB(2) receptors

Control of Breast Cancer by the Endocannabinoid System

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“Activation of the endocannabinoid system through CB1, CB2 and additional receptor subtypes results in the inhibition of a broad range of cancers.

The endocannabinoid system was discovered through research focusing on the classical cannabinoid agonist, ?9-tetrahydrocannabinol (?9-THC), and other synthetic cannabinoids.

This proposal will focus on the potential treatment of human breast cancer using cannabinoids as selective antitumor agents.

We have found that cannabinoid compounds activating CB1, CB2 and additional receptor subtypes can inhibit breast cancer cell proliferation and invasiveness and we have discovered down-stream targets that potentially link cannabinoid receptor stimulation to these effects.

Furthermore, our preliminary studies provide evidence that endogenous endocannabinoid tone tonically inhibits metastatic breast cancer cell proliferation and invasiveness through the activation of cannabinoid receptors.

Our preliminary data also suggests that cannabinoid compounds possess selective efficacy, having less adverse effects on the normal human cells from which the breast cancers arise.

Since toxicity in healthy tissue limits the efficacy of current cancer treatments, discovering the mechanism behind selective efficacy in human tissues is of clinical importance.

Cannabinoids can inhibit multiple types of tumor growth in vivo…

Testing the hypotheses outlined in the application may lead to the development of effective inhibitors of breast, and perhaps other, cancers.

This research may also elucidate novel mechanisms related to the anticancer activity of cannabinoids, and will serve to develop the career of the candidate in the field of cancer biology.”

 http://grantome.com/grant/NIH/K01-CA111723-01A2

http://www.thctotalhealthcare.com/category/breast-cancer/

Endocannabinoids and the Cardiovascular System in Health and Disease.

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“The endocannabinoid system is widely distributed throughout the cardiovascular system.

Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders.

In shock, endocannabinoids released within blood mediate the associated hypotension through CB1 activation. In hypertension, there is evidence for changes in the expression of CB1, and CB1 antagonism reduces blood pressure in obese hypertensive and diabetic patients.

The endocannabinoid system is also upregulated in cardiac pathologies.

This is likely to be cardioprotective, via CB2 and CB1 (lesser extent).

In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids.

Endocannabinoids have positive (CB2) and negative effects (CB1) on the progression of atherosclerosis. However, any negative effects of CB1 may not be consequential, as chronic CB1 antagonism in large scale human trials was not associated with significant reductions in atheroma.

In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB1, CB2, TRPV1 and PPARα.

Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26408169

Biosynthesis and Fate of Endocannabinoids.

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“Since the discovery of the two cannabinoid receptors, CB1 and CB2, several molecules, commonly defined as endocannabinoids, able to bind to and functionally activate these receptors, have been discovered and characterized.

Although the general thought was that the endocannabinoids were mainly derivatives of the n-6 fatty acid arachidonic acid, recent data have shown that also derivatives (ethanolamides) of n-3 fatty acids may be classified as endocannabinoids.

Whether the n-3 endocannabinoids follow the same biosynthetic and metabolic routes of the n-6 endocannabinoids is not yet clear and so warrants further investigation.

In this review, we describe the primary biosynthetic and metabolic pathways for the two well-established endocannabinoids, anandamide and 2-arachidonoylglycerol.”

http://www.ncbi.nlm.nih.gov/pubmed/26408157

Endocannabinoids and Their Pharmacological Actions.

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“The endocannabinoid system consists of G protein-coupled cannabinoid CB1 and CB2 receptors, of endogenous compounds known as endocannabinoids that can target these receptors, of enzymes that catalyse endocannabinoid biosynthesis and metabolism, and of processes responsible for the cellular uptake of some endocannabinoids.

This review presents in vitro evidence that most or all of the following 13 compounds are probably orthosteric endocannabinoids since they have all been detected in mammalian tissues in one or more investigation, and all been found to bind to cannabinoid receptors, probably to an orthosteric site: anandamide, 2-arachidonoylglycerol, noladin ether, dihomo-γ-linolenoylethanolamide, virodhamine, oleamide, docosahexaenoylethanolamide, eicosapentaenoylethanolamide, sphingosine, docosatetraenoylethanolamide, N-arachidonoyldopamine, N-oleoyldopamine and haemopressin.

In addition, this review describes in vitro findings that suggest that the first eight of these compounds can activate CB1 and sometimes also CB2 receptors and that another two of these compounds are CB1 receptor antagonists (sphingosine) or antagonists/inverse agonists (haemopressin).

Evidence for the existence of at least three allosteric endocannabinoids is also presented. These endogenous compounds appear to target allosteric sites on cannabinoid receptors in vitro, either as negative allosteric modulators of the CB1 receptor (pepcan-12 and pregnenolone) or as positive allosteric modulators of this receptor (lipoxin A4) or of the CB2 receptor (pepcan-12).

Also discussed are current in vitro data that indicate the extent to which some established or putative orthosteric endocannabinoids seem to target non-cannabinoid receptors and ion channels, particularly at concentrations at which they have been found to interact with CB1 or CB2 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/26408156

Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis.

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“Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA.

Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol.

These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides.

In addition, many cell types in synovial tissue express CB1 and TRPs.

In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation.

We demonstrate how CB1 agonism or antagonism can modulate arthritic disease.

The concept of functional antagonism with continuous CB1 activation is discussed.

Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied.

Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26343051

Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence.

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“Cannabinoid compounds include phytocannabinoids, endocannabinoids, and synthetics.

The two primary phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with CB1 receptors in the brain and peripheral tissue and CB2 receptors in the immune and hematopoietic systems.

The route of delivery of cannabis is important as the bioavailability and metabolism are very different for smoking versus oral/sublingual routes.

Gold standard clinical trials are limited; however, some studies have thus far shown evidence to support the use of cannabinoids for some cancer, neuropathic, spasticity, acute pain, and chronic pain conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/26325482

Effect of anandamide on endometrial adenocarcinoma (Ishikawa) cell numbers: implications for endometrial cancer therapy.

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“We have previously shown that patients with endometrial carcinoma express elevated concentrations of the endocannabinoid, anandamide (AEA), in both their plasma and their endometrial tissue and that the endometrial carcinoma cell line, Ishikawa, contains the receptors to which AEA binds.

Several studies have reported that human and rodent cancer cell lines die in response to high AEA concentrations.

The incidence of endometrial carcinoma continues to escalate and, although surgical treatment has improved, morbidity and mortality rates have not. A move towards a novel non-surgical therapeutic option is thus required, and the endocannabinoid system provides a good candidate target.

We aimed to investigate the effects of AEA on the survival and proliferation of an endometrial carcinoma cell model.

Our results show that AEA induces a decrease in Ishikawa cell number probably through inhibition of cell proliferation rather than cell death.

These data suggest that the increased plasma and tissue AEA concentrations observed in patients with endometrial cancer is a counter mechanism against further cancer growth and points to the endocannabinoid system as a potentially new therapeutic target.”

http://www.ncbi.nlm.nih.gov/pubmed/26312842

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60335-X/fulltext

Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal-Accumbens Plasticity after Stress.

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“Acute stress results in release of glucocorticoids which are potent modulators of learning and plasticity. This process is presumably mediated by the basolateral amygdala (BLA) where cannabinoids CB1 receptors play a key role in regulating the hypothalamic-pituitary-adrenal (HPA) axis.

Growing attention has been focused on nucleus accumbens (NAc) plasticity which regulates mood and motivation. The NAc integrates affective and context dependent input from the BLA and ventral subiculum (vSub), respectively.

Since our previous data suggest that the CB1/2 receptor agonist WIN55,212-2 (WIN) and glucocorticoid receptor (GR) antagonist RU-38486 (RU) can prevent the effects of stress on emotional memory, we examined whether intra-BLA WIN and RU can reverse the effects of acute stress on NAc plasticity…

The results suggest that glucocorticoid and cannabinoid systems in the BLA can restore normal function of the NAc and hence may play a central role in the treatment of a variety of stress-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26289146

The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases.

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“Endocannabinoids (eCBs) are endogenous lipid ligands that bind to cannabinoid receptors that also mediate the effects of marijuana.

The eCB system is comprised of eCBs, anandamide, and 2-arachidonoyl glycerol, their cannabinoid-1 and cannabinoid-2 receptors (CB1 and CB2, respectively), and the enzymes involved in their biosynthesis and degradation.

It is present in both the central nervous system and peripheral organs including the kidney.

The current review focuses on the role of the eCB system in normal kidney function and various diseases, such as diabetes and obesity, that directly contributes to the development of renal pathologies.

Normally, activation of the CB1 receptor regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments. In various mouse and rat models of obesity and type 1 and 2 diabetes mellitus, eCBs generated in various renal cells activate CB1 receptors and contribute to the development of oxidative stress, inflammation, and renal fibrosis.

These effects can be chronically ameliorated by CB1 receptor blockers.

In contrast, activation of the renal CB2 receptors reduces the deleterious effects of these chronic diseases.

Because the therapeutic potential of globally acting CB1 receptor antagonists in these conditions is limited due to their neuropsychiatric adverse effects, the recent development of peripherally restricted CB1 receptor antagonists may represent a novel pharmacological approach in treating renal diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26280171

Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.

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“Cannabinoid receptor 2 (CB2) selective agonists and inverse agonists possess significant potential as therapeutic agents for regulating inflammation and immune function.

Although CB2 agonists have received the greatest attention, it is emerging that inverse agonists also manifest anti-inflammatory activity.

In process of designing new cannabinoid ligands we discovered that the 2,6-dihydroxy-biphenyl-aryl methanone scaffold imparts inverse agonist activity at CB2 receptor without functional activity at CB1. To further explore the scaffold we synthesized a series of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone analogs and evaluated the CB1 and CB2 affinity, potency, and efficacy.

The studies reveal that an aromatic C ring is required for inverse agonist activity and that substitution at the 4 position is optimum. The resorcinol moiety is required for optimum CB2 inverse agonist activity and selectivity. Antagonist studies against CP 55,940 demonstrate that the compounds 41 and 45 are noncompetitive antagonists at CB2.”

http://www.ncbi.nlm.nih.gov/pubmed/26275680