Immunohistochemical analysis of cannabinoid receptor 1 expression in steatotic rat livers.

Posted on April 14, 2016 by David

“The primary aim of the present study was to determine the expression levels of cannabinoid receptor type 1 (CB1) in steatotic rat livers. The secondary aim was to clarify whether steatosis and inflammation are more marked in areas with increased CB1 overexpression.

The expression of CB1 and the number of cells overexpressing CB1 were determined. Steatosis was scored according to the Dixon scoring system.

CB1 overexpression and steatosis were detected in hepatocytes from all 38 livers sampled. The expression of CB1 was more marked in hepatocytes localized next to portal triads. Near the central veins, the expression was significantly weaker. Steatosis was more marked in areas of increased CB1 overexpression. Lymphocyte infiltration was more commonly observed in areas of increased CB1 overexpression.

Therefore, the present results indicate that CB1 receptors are overexpressed in areas with steatosis, and indicate that CB1 in hepatocytes contributes to the formation of steatosis in rats, even prior to its progression to steatohepatitis.

These results are consistent with publications reporting that CB1 in hepatocytes increases lipogenesis and contributes to inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/27073427

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

Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling.

Posted on April 14, 2016 by David

“In the hypothalamic arcuate nucleus (ARC), proopiomelanocortin (POMC) neurons and the POMC-derived peptide α-melanocyte-stimulating hormone (α-MSH) promote satiety. POMC neurons receive orexin-A (OX-A)-expressing inputs and express both OX-A receptor type 1 (OX-1R) and cannabinoid receptor type 1 (CB₁R) on the plasma membrane.

OX-A is crucial for the control of wakefulness and energy homeostasis and promotes, in OX-1R-expressing cells, the biosynthesis of the endogenous counterpart of marijuana’s psychotropic and appetite-inducing component Δ⁹-tetrahydrocannabinol, i.e., the endocannabinoid 2-arachidonoylglycerol (2-AG), which acts at CB₁R.

We report that OX-A/OX-1R signaling at POMC neurons promotes 2-AG biosynthesis, hyperphagia, and weight gain by blunting α-MSH production via CB₁R-induced and extracellular-signal-regulated kinase 1/2 activation- and STAT3 inhibition-mediated suppression ofPomcgene transcription. Because the systemic pharmacological blockade of OX-1R by SB334867 caused anorectic effects by reducing food intake and body weight, our results unravel a previously unsuspected role for OX-A in endocannabinoid-mediated promotion of appetite by combining OX-induced alertness with food seeking. Notably, increased OX-A trafficking was found in the fibers projecting to the ARC of obese mice (ob/oband high-fat diet fed) concurrently with elevation of OX-A release in the cerebrospinal fluid and blood of mice.

Furthermore, a negative correlation between OX-A and α-MSH serum levels was found in obese mice as well as in human obese subjects (body mass index > 40), in combination with elevation of alanine aminotransferase and γ-glutamyl transferase, two markers of fatty liver disease.

These alterations were counteracted by antagonism of OX-1R, thus providing the basis for a therapeutic treatment of these diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27071101

Cannabinoid receptor 1 controls human mucosal-type mast cell degranulation and maturation in situ.

Posted on April 12, 2016 by David

“Because many chronic inflammatory and allergic disorders are intimately linked to excessive mast cell (MC) numbers and activation, it is clinically important to understand the physiologic mechanisms preventing excess MC accumulation/degranulation in normal human tissues.

Because endocannabinoids are increasingly recognized as neuroendocrine regulators of MC biology, we investigated how cannabinoid receptor (CB) 1 signaling affects human mucosal-type mast cells (hMMCs).

In human airway mucosa hMMC activation and maturation are subject to a potent inhibitory endocannabinoid tone through CB1 stimulation.

This invites one to target the endocannabinoid system in human airway mucosa as a novel strategy in the future management of allergic diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/23453134

MAPPING CANNABINOID RECEPTOR 1 ALLOSTERIC SITE(S): CRITICAL MOLECULAR DETERMINANT AND SIGNALING PROFILE OF GAT100 – A NOVEL, POTENT AND IRREVERSIBLY BINDING PROBE.

Posted on April 6, 2016 by David

“One of the most abundant G-protein coupled receptors (GPCRs) in brain, the cannabinoid 1 receptor (CB1R) is a tractable therapeutic target for treating diverse psychobehavioral and somatic disorders.

Adverse on-target effects associated with small-molecule CB1R orthosteric agonists and inverse agonists/antagonists have plagued their translational potential. Allosteric CB1R modulators offer a potentially safer modality through which CB1R signaling may be directed for therapeutic benefit.

Rational design of candidate, drug-like CB1R allosteric modulators requires greater understanding of the architecture of the CB1R allosteric endodomain(s) and the capacity of CB1R allosteric ligands to tune the receptor’s information output.

These data help inform the engineering of newer-generation, druggable CB1R allosteric modulators and demonstrate the utility of GAT100 as a covalent probe for mapping structure-function correlates characteristic of the druggable CB1R allosteric space.”

http://www.ncbi.nlm.nih.gov/pubmed/27046127

Endocannabinoid Signaling Regulates Sleep Stability.

Posted on April 1, 2016 by David

“Since antiquity cannabinoids have been used as a treatment for insomnia, and the first reports in western medical literature regarding the therapeutic utility and physiological effects of cannabis preparations note their hypnogenic properties.

The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized.

We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system.

Our findings demonstrate that eCB signaling is necessary and sufficient for the control of sleep stability, but this neurotransmitter system is not necessary for sleep homeostasis.

These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816426/

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

Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation?

Posted on March 30, 2016 by David

“The Cannabis sativa plant has been used to treat various physiological and psychiatric conditions for millennia.

Current research is focused on isolating potentially therapeutic chemical constituents from the plant for use in the treatment of many central nervous system disorders.

Of particular interest is the primary nonpsychoactive constituent cannabidiol (CBD).

Unlike Δ9-tetrahydrocannabinol (THC), CBD does not act through the cannabinoid type 1 (CB1) receptor but has many other receptor targets that may play a role in psychiatric disorders.

Here we review preclinical and clinical data outlining the therapeutic efficacy of CBD for the treatment of motivational disorders such as drug addiction, anxiety, and depression.

Across studies, findings suggest promising treatment effects and potentially overlapping mechanisms of action for CBD in these disorders and indicate the need for further systematic investigation of the viability of CBD as a psychiatric pharmacotherapy.”

http://www.ncbi.nlm.nih.gov/pubmed/27023732

Cannabinoids Occlude the HIV-1 Tat-Induced Decrease in GABAergic Neurotransmission in Prefrontal Cortex Slices.

Posted on March 20, 2016 by David

“In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is now considered a chronic disease that specifically targets the brain and causes HIV-1-associated neurocognitive disorders (HAND).

Endocannabinoids exhibit neuroprotective and anti-inflammatory properties in several central nervous system (CNS) disease models, but their effects in HAND are poorly understood.

Results indicated a Tat-induced decrease in GABAergic neurotransmission, which was occluded by cannabinoids via a CB₁R-related mechanism.

Understanding the relationship between Tat toxicity and endocannabinoid signaling has the potential to identify novel therapeutic interventions to benefit individuals suffering from HAND and other cognitive impairments.”

http://www.ncbi.nlm.nih.gov/pubmed/26993829

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

[Role of cannabinoid receptors in renal diseases].

Posted on March 13, 2016 by David

“Chronic kidney disease remains a major challenge for public health systems and corresponds to the replacement of renal functional tissue by extracellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for chronic kidney disease except nephroprotective strategies.

The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in chronic kidney disease.

Experimental data obtained in models of diabetes and obesity suggested that CB1 blockade and CB2 stimulation may slow the development of diabetic nephropathy.

In human kidneys, CB1 expression is increased in various chronic nephropathies and correlates with renal function. Moreover, endogenous CB1 and CB2 ligands are greatly increased during renal fibrogenesis. A microarray analysis performed in an experimental model of renal fibrosis found that the gene encoding for the CB1 receptor was among the most upregulated genes. We also demonstrated that renal fibrogenesis could be reduced by CB1 inhibition and CB2 stimulation in an experimental model through a direct mechanism involving CB1 on myofibroblasts, which are the major effector cells during renal fibrosis.

Therefore, CB1 blockers may represent a novel therapeutic target in chronic kidney disease and diabetes.”

http://www.ncbi.nlm.nih.gov/pubmed/26968477

Cannabinoids inhibit insulin receptor signaling in pancreatic β-cells.

Posted on March 12, 2016 by David

“Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting β-cells in the islets of Langerhans. Insulin itself positively regulates β-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway.

It is now coming to light that cannabinoid 1 receptor (CB1R) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CB1Rs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate β-cell proliferation and if they influence insulin action.

These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of β-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and proliferation in diabetes.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064093/

Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic β Cells.

Posted on March 12, 2016 by David

“Recent reports have shown that cannabinoid 1 receptors (CB1Rs) are expressed in pancreatic β cells, where they induce cell death and cell cycle arrest by directly inhibiting insulin receptor activation. Here, we report that CB1Rs regulate the expression of the anti-apoptotic protein Bcl-2 and cell cycle regulator cyclin D2 in pancreatic β cells. Treatment of MIN6 and βTC6 cells with a synthetic CB1R agonist, WIN55,212-2, led to a decrease in the expression of Bcl-2 and cyclin D2, in turn inducing cell cycle arrest in G0/G1 phase and caspase-3-dependent apoptosis. Additionally, genetic deletion and pharmacological blockade of CB1Rs after injury in mice led to increased levels of Bcl-2 and cyclin D2 in pancreatic β cells. These findings provide evidence for the involvement of Bcl-2 and cyclin D2 mediated by CB1Rs in the regulation of β-cell survival and growth, and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and growth in diabetes.”

http://www.ncbi.nlm.nih.gov/pubmed/26967640