Cannabinoid receptors as therapeutic targets for dialysis-induced peritoneal fibrosis.

Posted on March 12, 2015 by David

“Long-term exposure to bioincompatible peritoneal dialysis solutions is frequently complicated with peritoneal fibrosis and ultrafiltration failure.

As cannabinoid receptor (CBR) ligands have been reported to be beneficial to ameliorate the process of liver fibrosis, we strove to investigate their therapeutic potential to prevent peritoneal fibrosis…

Intraperitoneal administration of CBR ligands (CB(1)R antagonist and CB(2)R agonist) offers a potential therapeutic strategy to reduce dialysis-induced peritoneal fibrosis and to prolong the peritoneal survival in peritoneal dialysis patients.”

http://www.ncbi.nlm.nih.gov/pubmed/23296044

Cannabinoid receptor 1 is a major mediator of renal fibrosis.

Posted on March 12, 2015 by David

“Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health.

There is a need to explore new therapeutic pathways to reduce renal fibrogenesis.

To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys.

The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney.

Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-β1 stimulation.

The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis.

Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.”

http://www.ncbi.nlm.nih.gov/pubmed/25760323

Cannabinoid signaling and liver therapeutics.

Posted on February 19, 2015 by David

Journal of Hepatology Home

“Over the last decade, the endocannabinoid system has emerged as a pivotal mediator of acute and chronic liver injury, with the description of the role of CB1 and CB2 receptors and their endogenous lipidic ligands in various aspects of liver pathophysiology.

A large number of studies have demonstrated that CB1 receptor antagonists represent an important therapeutic target, owing to beneficial effects on lipid metabolism and in light of its antifibrogenic properties.

Unfortunately, the brain-penetrant CB1 antagonist rimonabant, initially approved for the management of overweight and related cardiometabolic risks, was withdrawn because of an alarming rate of mood adverse effects.

However, the efficacy of peripherally-restricted CB1 antagonists with limited brain penetrance has now been validated in preclinical models of NAFLD, and beneficial effects on fibrosis and its complications are anticipated.

CB2 receptor is currently considered as a promising anti-inflammatory and antifibrogenic target, although clinical development of CB2 agonists is still awaited.

In this review, we highlight the latest advances on the impact of the endocannabinoid system on the key steps of chronic liver disease progression and discuss the therapeutic potential of molecules targeting cannabinoid receptors…

Overwhelming evidence supports the therapeutic potential of peripherally-restricted CB1 antagonists and CB2 agonists in the management of chronic liver diseases.”

http://www.journal-of-hepatology.eu/article/S0168-8278(13)00212-2/fulltext

http://www.thctotalhealthcare.com/category/liver-disease/

Neural Effects of Cannabinoid CB1 Neutral Antagonist Tetrahydrocannabivarin (THCv) on Food Reward and Aversion in Healthy Volunteers.

Posted on December 30, 2014 by David

“Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders.

We previously showed that the cannabis receptor (CB1) inverse agonist rimonabant, an anti-obesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses. Unlike rimonabant, tetrahydrocannabivarin (THCv) is a neutral CB1 receptor antagonist and may therefore produce different modulations of the neural reward system…

Conclusions: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv increases neural responding to rewarding and aversive stimuli.

This effect profile suggests therapeutic activity in obesity, perhaps with a lowered risk of depressive side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/25542687

http://www.thctotalhealthcare.com/category/obesity-2/

Cannabinoid receptor type 2 activation in atherosclerosis and acute cardiovascular diseases.

Posted on September 24, 2014 by David

“In the last decades, the cannabinoid system (comprising synthetic and endogenous cannabinoid agonists and antagonists, their receptors and degrading enzymes) has been shown to induce potent immunomodulatory activities in atherogenesis and acute ischemic complications.

Differently from the other cannabinoid receptors in which controversial results are reported, the selective activation of the cannabinoid receptor type 2 (CB2) has been shown to play anti-inflammatory and protective actions within atherosclerotic vessels and downstream ischemic peripheral organs.

CB2 is a transmembrane receptor that triggers protective intracellular pathways in cardiac, immune and vascular cells in both in human and animal models of atherosclerosis…

medications activating CB2 function in the circulation or peripheral target organs might be a promising approach against atherogenesis.

This review updates evidence from preclinical studies on different CB2-triggered pathways in atherosclerosis and acute ischemic events.”

http://www.ncbi.nlm.nih.gov/pubmed/25245379

Cannabinoid Receptor Type 1 Antagonist, AM251, Attenuates Mechanical Allodynia and Thermal Hyperalgesia after Burn Injury.

Posted on September 5, 2014 by David

“Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain.

CONCLUSIONS::

AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors.”

http://www.ncbi.nlm.nih.gov/pubmed/25188001

Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling.

Posted on July 27, 2014 by David

Figure 1.

“To further investigate the role of the cannabinoid system in pilosebaceous unit biology, we have explored in the current study whether and how endocannabinoids have an impact on human sebaceous gland biology…

Here, we provide the first evidence that SZ95 sebocytes express CB2 but not CB1…

…our results collectively suggest that human sebocytes utilize a paracrine-autocrine, endogenously active, CB2-mediated endocannabinoid signaling system for positively regulating lipid production and cell death.

CB2 antagonists or agonists therefore deserve to be explored in the management of skin disorders characterized by sebaceous gland dysfunctions (e.g., acne vulgaris, seborrhea, dry skin).”

http://www.fasebj.org/content/22/10/3685.long

[A role for the endocannabinoid system in hepatic steatosis].

Posted on July 24, 2014 by David

“The endocannabinoid system (SEC) is an important modulator of several metabolic functions.

This system is composed by cannabinoid receptors type 1 and 2 (RCB1 and RCB2), their endogenous ligands, known as endocannabinoids, and the enzymes involved in their synthesis and degradation. A deregulated SEC originates metabolic alterations in several tissues, resulting in the typical manifestations of the metabolic syndrome…

In this review we discuss the proposed mechanisms by which SEC is involved in the etiology of hepatic steatosis, as well as the therapeutic possibilities involving peripheral RCB1/RCB2 antagonism/agonism, for the treatment of this condition.”

http://www.ncbi.nlm.nih.gov/pubmed/25052273

http://www.thctotalhealthcare.com/category/hepatic-steatosis/

Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host targeting agents.

Posted on July 24, 2014 by David

“Direct acting antivirals have significantly improved treatment outcomes in chronic hepatitis C (CHC), but side effects, drug resistance and cost mean that better treatments are still needed.

Lipid metabolism is closely linked with hepatitis C virus (HCV) replication and endocannabinoids are major regulators of lipid homeostasis.

The cannabinoid 1 (CB1) receptor mediates these effects in the liver.

Here we investigated whether CB1 blockade inhibits HCV replication.

The antiviral effect of a CB1 antagonist, AM251 was examined…

Treatment with AM251 strongly inhibited HCV RNA (~70%), viral protein (~80%), the production of new virus particles (~70%), and virus infectivity (~90%)…

We suggest that CB1 antagonists may represent an entirely new class of drugs with activity against HCV.

http://www.ncbi.nlm.nih.gov/pubmed/25053565

http://www.thctotalhealthcare.com/category/hepatitis/

Long-term cannabinoid type 2 receptor agonist therapy decreases Bacterial Translocation In Rats with cirrhosis and ascites.

Posted on June 24, 2014 by David

“Intestinal hyper-permeability, impaired peritoneal macrophages (PMs) phagocytosis, and, bacterial translocation (BT) resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP), together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications.

Manipulation of cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokines release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats…

CONCLUSIONS:

Our study suggests that CB2R agonist have the potential to treat BT and various relevant abnormalities through the inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα releases in cirrhosis. Overall, chronic CB2R agonist treatment affects multiple approach mechanisms, and the direct effect on hyperdynamic circulation is only minor.”

http://www.ncbi.nlm.nih.gov/pubmed/24953022