Tag Archives: endocannabinoids

Endocannabinoid overactivity and intestinal inflammation

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Abstract

“Cannabinoid receptors of type 1 and 2 (CB1 and CB2), endogenous ligands that activate them (endocannabinoids), and mechanisms for endocannabinoid biosynthesis and inactivation have been identified in the gastrointestinal system. Activation of CB1 receptors by endocannabinoids produces relaxation of the lower oesophageal sphincter and inhibition of gastric acid secretion, intestinal motility, and fluid stimulated secretion. However, stimulation of cannabinoid receptors impacts on gastrointestinal functions in several other ways. Recent data indicate that the endocannabinoid system in the small intestine and colon becomes over stimulated during inflammation in both animal models and human inflammatory disorders. The pathological significance of this “endocannabinoid overactivity” and its possible exploitation for therapeutic purposes are discussed here.”

 

“The endocannabinoid system of the gastrointestinal tract includes not only cannabinoid receptors but also endogenous agonists of these receptors, as well as mechanisms for their biosynthesis and inactivation”

 

“The main psychotropic constituent of the plant Cannabis sativa and marijuana, Δ9‐tetrahydrocannabinol, exerts its pharmacological effects by activating two G protein coupled cannabinoid receptors.1These are the CB1 receptor, present in central and peripheral nerves (including the human enteric nervous system), and the CB2 receptor, expressed abundantly in immune cells. In rodents, CB1 receptor immunoreactivity has been detected in discrete nuclei of the dorsovagal complex (involved in emesis), and in efferents from the vagal ganglia and in enteric (myenteric and submucosal) nerve terminals where they inhibit excitatory (mainly cholinergic) neurotransmission. In vivo pharmacological studies have shown that activation of CB1 receptors reduces emesis, produces inhibition of gastric acid secretion8 and relaxation of the lower oesophageal sphincter (two effects that might be beneficial in the treatment of gastro‐oesophageal reflux disease), and inhibits intestinal motility and secretion. Consistent with immunohistochemical data showing that CB2 receptors are particularly evident in colonic tissues from patients with inflammatory bowel diseases (IBD), evidence suggests that CB2 inhibits intestinal motility during certain pathological states.1″

 

“…endocannabinoids convey protection from enteric hypersecretory states (for example, cholera toxin induced diarrhoea), which is in agreement with anecdotal reports from folk medicine on the use of Cannabis sativa in the treatment of diarrhoea.“

 

“Overactivity of the endocannabinoid system is becoming a well established concept in human intestinal conditions with an inflammatory component”

   

“The inhibitory effects of cannabinoids on intestinal inflammation, as well as on intestinal motility and secretory diarrhoea, observed in preclinical studies, increase the potential for their use in the treatment of IBD”

  

“There is great potential for the development of new therapeutic agents against intestinal inflammation from the endocannabinoid system”

 

“Conclusions: new therapies for the treatment of IBD from the endocannabinoid system”

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856409/

Brain’s own cannabis compound protects against inflammation

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“Some clinical studies have indicated that marijuana or its active cannabinoid ingredient alleviates symptoms of the inflammatory disease multiple sclerosis (MS). Also, researchers have found that the brain’s natural “endocannabinoids” are released after brain injury and are believed to alleviate neuronal damage. However, scientists have not understood how such substances act within the brain’s own immune system.

 Now, experiments by Oliver Ullrich and colleagues have pinpointed how one of the brain’s endocannabinoids protects neurons from inflammation after such damage. They say their studies could lead to new drugs to treat the inflammation and brain degeneration from MS or other such disorders.

In an article in the January 5, 2006, issue of Neuron, the researchers reported experiments showing how the endocannabinoid anandamide (AEA) protects brain cells from inflammation. Such a role in the brain’s immune system is distinct from cannabinoids’ effects on neuronal signaling that produce the behavioral effects of marijuana.”

http://www.bio-medicine.org/biology-news/Brains-own-cannabis-compound-protects-against-inflammation-2810-1/

The role of cannabinoid system on immune modulation: therapeutic implications on CNS inflammation.

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Abstract

“There is a growing amount of evidence suggesting that cannabinoids may be neuroprotective in CNS inflammatory conditions. Advances in the understanding of the physiology and pharmacology of the cannabinoid system have increased the interest of cannabinoids as potential therapeutic targets. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in cells of the immune system, as well as in brain glial cells. In the present review it is summarized the effects of cannabinoids on immune reactivity and on the regulation of neuroinflammatory processes associated with brain disorders with special attention to chronic inflammatory demyelinating diseases such as multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/16026313

Endocannabinoids and the regulation of their levels in health and disease.

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Abstract

“PURPOSE OF REVIEW:

Endocannabinoids are defined as endogenous agonists of cannabinoid receptors, that is, of the two G-protein-coupled receptors for the Cannabis psychoactive principle Delta-tetra-hydrocannabinol. Two such endogenous mediators have been most thoroughly studied so far: anandamide and 2-arachidonoylglycerol. Here we review the mechanisms for the regulation of their levels under physiological and pathological conditions, and recent findings on their role in disease.

RECENT FINDINGS:

It is becoming increasingly clear that, although both anandamide and 2-arachidonoyl-glycerol are produced and degraded ‘on demand’, the levels of these two compounds appear to be regulated in different, and sometimes even opposing, ways, often using redundant molecular mechanisms. Alterations of endocannabinoid levels have been found in both animal models of pain, neurological and neurodegenerative states, gastrointestinal disorders and inflammatory conditions, and in blood, cerebrospinal fluid and bioptic samples from patients with various diseases.

SUMMARY:

Endocannabinoid levels appear to be transiently elevated as an adaptive reaction to re-establish normal homeostasis when this is acutely and pathologically perturbed. In some chronic conditions, however, this system also contributes to the progress or symptoms of the disorder. As a consequence, new therapeutic drugs are being designed from both stimulants and blockers of endocannabinoid action.”

http://www.ncbi.nlm.nih.gov/pubmed/17353660

From endocannabinoid profiling to ‘endocannabinoid therapeutics’.

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Abstract

“The discovery of the endocannabinoid signalling system, that is, of cannabinoid receptors, their endogenous ligands, known as endocannabinoids, and of endocannabinoid anabolic and catabolic enzymes, raised several questions regarding the physiopathological role of these mediators. Several of these questions were answered by investigating alterations in the levels of the most studied endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in tissues of animal models of disorders, and in bioptic samples and biological fluids (cerebrospinal fluid and blood) of human volunteers. Subsequently, the pharmacological effects of synthetic compounds that selectively target the cannabinoid CB(1) and CB(2) receptors, and endocannabinoid anabolic and catabolic enzymes, established cause-effect relationships between pathological alterations in endocannabinoid levels and the symptoms and progress of several disorders, including emesis, obesity, metabolic disorders, hepatic diseases, pain, inflammation and neurological and neuropsychiatric disorders. These new developments are discussed in this second review on the endocannabinoids, together with the results of pre-clinical and clinical studies on the potential therapeutic use of plant-derived cannabinoids and synthetic agents that manipulate pharmacologically the action at cannabinoid receptors or the tissue levels of AEA and 2-AG.”

http://www.ncbi.nlm.nih.gov/pubmed/19497779

Endocannabinoids Measurement in Human Saliva as Potential Biomarker of Obesity

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Background

“The discovery of the endocannabinoid system and of its role in the regulation of energy balance has significantly advanced our understanding of the physiopathological mechanisms leading to obesity and type 2 diabetes. New knowledge on the role of this system in humans has been acquired by measuring blood endocannabinoids. Here we explored endocannabinoids and related N-acylethanolamines in saliva and verified their changes in relation to body weight status and in response to a meal or to body weight loss.”

“The discovery of the endocannabinoid system (ECS) and of its impact on the regulation of energy homeostasis represents a significant advance in the study of obesity and type 2 diabetes [1]–[4].”

“The saliva is the first digestive secretion produced in response to the ingestion of food [11]. Therefore, it is reasonable to investigate whether signals and systems involved in the regulation of food intake, such as the ECS, might be present in saliva and exert a functional role. Besides, saliva offers distinctive advantages over serum or plasma as a diagnostic tool, thanks to the non-invasiveness of the collection procedure.”

“The ECS is present in human salivary glands.”

“Changes in salivary endocannabinoids and N-acylethanolamines levels in response to body weight loss.”

“Here we demonstrate that endocannabinoids and related N-acylethanolamines can be reliably detected and quantified in human saliva. Similarly to what already reported for circulating levels in the blood [7], [9], [10], the salivary concentration of AEA and OEA were significantly increased in obese, insulin-resistant subjects as compared to normal weight controls.”

“the present findings overall indicate that salivary AEA might be a useful biomarker in human obesity, in particular considering that salivary samples are easy to collect, require a non-invasive procedure advantageous when performing studies in obese subjects in whom venipuncture may be difficult, and can be repeatedly collected at home by the patient during a therapeutic intervention. This type of tool could therefore be used to better phenotype the obese population, assess responses to treatment, or to further study the physiology of the ECS in humans, by investigating salivary endocannabinoid responses under various conditions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409167/

Cannabinoid signalling regulates inflammation and energy balance: the importance of the brain-gut axis.

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Abstract

“Energy balance is controlled by centres of the brain which receive important inputs from the gastrointestinal tract, liver, pancreas, adipose tissue and skeletal muscle, mediated by many different signalling molecules. Obesity occurs when control of energy intake is not matched by the degree of energy expenditure. Obesity is not only a state of disordered energy balance it is also characterized by systemic inflammation. Systemic inflammation is triggered by the leakage of bacterial lipopolysaccharide through changes in intestinal permeability. The endocannabinoid system, consisting of the cannabinoid receptors, endogenous cannabinoid ligands and their biosynthetic and degradative enzymes, plays vital roles in the control of energy balance, the control of intestinal permeability and immunity. In this review we will discuss how the endocannabinoid system, intestinal microbiota and the brain-gut axis are involved in the regulation of energy balance and the development of obesity-associated systemic inflammation. Through direct and indirect actions throughout the body, the endocannabinoid system controls the development of obesity and its inflammatory complications.”

http://www.ncbi.nlm.nih.gov/pubmed/22269477

The endocannabinoid system : a new target for the regulation of energy balance and metabolism.

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Abstract

“Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism through the central control of appetite and by affecting peripheral metabolism. Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor, is believed to be responsible for the majority of the central effects of endocannaboids on appetite. Chronic positive energy balance and obesity have been associated with an overactivation of the endocannaboid system which has been suggested to contribute to the development of abdominal obesity and to associated metabolic abnormalities which increase the risk of cardiovascular disease and type 2 diabetes. Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver. Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss. Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly, to “fix” the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk.”

http://www.ncbi.nlm.nih.gov/pubmed/17667864

[Endocannabinoid system and energy metabolism: physiology and pathophysiology].

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Abstract

“The ability of the endocannabinoid system to control appetite, food intake and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system has recently been shown to control several metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, therefore drugs interfering with this overactivation by blocking CB1 receptor are considered as valuable candidates for the treatment of obesity and related cardiometabolic risk factors.”

http://www.ncbi.nlm.nih.gov/pubmed/18773754

The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning?

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Abstract

“The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. This mini-review summarizes the main findings that supported the clinical use of CB1 antagonists/inverse agonists, the clinical concerns that have emerged, and the possible future of cannabinoid-based therapy of obesity and related diseases. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes, liver, skeletal muscle and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways. Obese people seem to display an increased endocannabinoid tone, driving CB(1) receptor in a feed-forward dysfunction. Several CB(1) antagonists/inverse agonists have been developed for the treatment of obesity. Although these drugs were found to be efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors, they resulted in adverse psychiatric effects that limited their use and finally led to the end of the clinical use of systemic CB(1) ligands with significant inverse agonist activity for complicated obesity. However, the existence of alternatives such as CB(1) partial agonists, neutral antagonists, antagonists restricted to the periphery, allosteric modulators and other potential targets within the ECS indicate that a cannabinoid-based therapy for the management of obesity and its associated cardiometabolic sequelae should remain open for consideration.”

http://www.ncbi.nlm.nih.gov/pubmed/20347862