Tag Archives: endocannabinoid system

Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis.

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“Toll-like receptors (TLRs) are the sensors of pathogen-associated molecules that trigger tailored innate immune intracellular signalling responses to initiate innate immune reactions.

Data from the experimental autoimmune encephalomyelitis (EAE) model indicates that TLR signalling machinery is a pivotal player in the development of murine EAE. To compound this, data from human studies indicate that complex interplay exists between TLR signalling and Multiple Sclerosis (MS) pathogenesis.

Cannabis-based therapies are in clinical development for the management of a variety of medical conditions, including MS. In particular Sativex®, a combination of plant-derived cannabinoids, is an oromucosal spray with efficacy in MS patients, particularly those with neuropathic pain and spasticity.

Despite this, the precise cellular and molecular mechanisms of action of Sativex® in MS patients remains unclear. This review will highlight evidence that novel interplay exists between the TLR and cannabinoid systems, both centrally and peripherally, with relevance to the pathogenesis of MS.”

http://www.ncbi.nlm.nih.gov/pubmed/27079840

Production of endocannabinoids by activated T cells and B cells modulates inflammation associated with delayed type hypersensitivity.

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“Endocannabinoids are endogenous ligands for the cannabinoid (CB) receptors which include anandamide (AEA) and (2-AG). 2-AG has been linked to inflammation due to its elevated expression in animal models of autoimmunity and hypersensitivity.

However, administration of exogenous 2-AG has been shown to suppress inflammation making its precise role unclear. In the current study, we investigated the role of 2-AG following immunization of C57BL/6 (BL6) mice with methylated BSA (mBSA) antigen, which triggers both delayed type hypersensitivity (DTH) and antibody response.

Together, these data show for the first time that activated T and B cells produce 2-AG, which plays a negative regulatory role to decrease DTH via inhibition of T-cell activation and proliferation.

Moreover, these findings suggest that exogenous 2-AG treatment can be used therapeutically in Th1- or Th17-driven disease.”  http://www.ncbi.nlm.nih.gov/pubmed/27064137

“∆9-Tetrahydrocannabinol (THC) is one of the major bioactive cannabinoids derived from the Cannabis sativa plant and is known for its anti-inflammatory properties. Delayed-type hypersensitivity (DTH) is driven by proinflammatory T helper cells including the classic inflammatory Th1 lineage as well as the more recently discovered Th17 lineage. In the current study, we investigated whether THC can alter the induction of Th1/Th17 cells involved in mBSA-induced DTH response… In summary, the current study suggests that THC treatment during DTH response can simultaneously inhibit Th1/Th17 activation via regulation of microRNA (miRNA) expression.• THC treatment inhibits simultaneous Th1/Th17 driven inflammation. • THC treatment corrects DTH-mediated microRNA dysregulation. • THC treatment regulates proinflammatory cytokines and transcription factors.” http://www.ncbi.nlm.nih.gov/pubmed/27038180

http://www.thctotalhealthcare.com/tag/anti-inflammatory/

Antitumorigenic targets of cannabinoids – current status and implications.

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“Molecular structures of the endocannabinoid system have gained interest as potential pharmacotherapeutical targets for systemic cancer treatment.

The present review covers the contribution of the endocannabinoid system to cancer progression. Particular focus will be set on the accumulating preclinical data concerning antimetastatic, anti-invasive and anti-angiogenic mechanisms induced by cannabinoids.

Expert opinion: The main goal of targeting endocannabinoid structures for systemic anticancer treatment is the comparatively good safety profile of cannabinoid compounds.

In addition, antitumorigenic mechanisms of cannabinoids are not restricted to a single molecular cascade but involve multiple effects on various levels of cancer progression such as angiogenesis and metastasis. Particularly the latter effect has gained interest for pharmacological interventions.

Thus, drugs aiming at the endocannabinoid system may represent potential “antimetastatics” for an upgrade of a future armamentarium against cancer diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27070944

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

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

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“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.

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“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

Analysis of endocannabinoid signaling elements and related proteins in lymphocytes of patients with Dravet syndrome.

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“Cannabidiol (CBD) reduces seizures in childhood epilepsy syndromes including Dravet syndrome (DS).

A formulation of CBD has obtained orphan drug designation for these syndromes and clinical trials are currently underway.

We believe of interest to investigate whether these potential targets are altered in DS, in particular whether the endocannabinoid system is dysregulated. To this end, lymphocytes from patients and controls were used for analysis of gene expression of transmitter receptors and transporters, ion channels, and enzymes associated with CBD effects, as well as endocannabinoid genes.

In conclusion, together with changes in the voltage-dependent calcium channel α-1h subunit, we found an upregulation of CB 2 receptors, associated with an activation of lymphocytes and changes in inflammation-related genes, in DS patients. Such changes were also reported in inflammatory disorders and may indirectly support the occurrence of a potential dysregulation of the endocannabinoid system in the brain.”

http://www.ncbi.nlm.nih.gov/pubmed/27069631

http://www.thctotalhealthcare.com/category/dravet-syndome/

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

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“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

Endocannabinoids and immune regulation

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“Cannabinoid pharmacology has made important advances in recent years after the discovery of the cannabinoid receptors.

These discoveries have added to our understanding of exogenous and endogenous cannabinoid signaling along with exploring the various pathways of their biosynthesis, molecular structure, inactivation, and anatomical distribution of their receptors throughout the body.

The endocannabinoid system is involved in immunoregulation and neuroprotection.

The discovery of cannabinoid receptors occurring naturally throughout the vertebrate body and the availability of highly selective and potent canabimimetics led to the identification of a naturally occurring lipid signaling system termed the endocannabinoid system.

Interestingly, the endocannabinoid system dates back very long in the evolution because it exists as an ancient plant signaling system regulating the plant immunity-related genes in response to infection and stress.

The main pharmacological functions of the endocannabinoid system include neuromodulation, controlling motor functions, cognition, emotional responses, homeostasis and motivation. However, in the periphery, this system is an important modulator of autonomic nervous system, the immune system and microcirculation.

There have been a number of recent studies which have demonstrated that the endocannabinoids have both inhibitory effects and stimulatory impact on the immune system and may be actually important in homeostasis or control of the immune reactions.

 The image of endocannabinoid system now appears to be of a modulatory complex which affects the physiological functions in peripheral tissues and can thus be considered as a potential therapeutic target in the future.
Thus, manipulation of endocannabinoids in vivo may constitute a novel treatment modality against inflammatory disorders.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044336/

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways.

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“Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair.

However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects.

EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists.

Furthermore, in NSCs derived from IL-1β deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1β signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1β deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways.

These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair.”

http://www.ncbi.nlm.nih.gov/pubmed/27044662

No more pain upon Gq-protein-coupled receptor activation: role of endocannabinoids.

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“Marijuana has been used to relieve pain for centuries.

The analgesic mechanism of its constituents, the cannabinoids, was only revealed after the discovery of cannabinoid receptors (CB1 and CB2) two decades ago.”

http://www.ncbi.nlm.nih.gov/pubmed/24494686