Endocannabinoid signaling in innate and adaptive immunity.

“The immune system can be modulated and regulated not only by foreign antigens but also by other humoral factors and metabolic products, which are able to affect several quantitative and qualitative aspects of immunity.

Among these, endocannabinoids are a group of bioactive lipids that might serve as secondary modulators, which when mobilized coincident with or shortly after first-line immune modulators, increase or decrease many immune functions.

Most immune cells express these bioactive lipids, together with their set of receptors and of enzymes regulating their synthesis and degradation.

In this review, a synopsis of the manifold immunomodulatory effects of endocannabinoids and their signaling in the different cell populations of innate and adaptive immunity is appointed, with a particular distinction between mice and human immune system compartments.”

http://www.ncbi.nlm.nih.gov/pubmed/25585882

Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation.

“Endocannabinoids are a family of lipid mediators that are involved in the regulation of gastrointestinal (GI) motility. The expression, localization and function of their biosynthetic enzymes in the GI tract are not well understood.

Here we examined the expression, localization and function of the enzyme diacylglycerol lipase (DAGLα), involved in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG).

Cannabinoid (CB)1-deficient, wildtype control and C3H/HeJ mice, a genetically constipated model, were used…

DAGLα is expressed in the enteric nervous system and its inhibition reverses slowed GI motility, intestinal contractility and constipation through 2-AG and CB1 receptor mediated mechanisms.

Our data suggest that DAGLα inhibitors may be promising candidates for the treatment of constipation.”

http://www.ncbi.nlm.nih.gov/pubmed/25684407

Palmitoyl Serine: An Endogenous Neuroprotective Endocannabinoid-Like Entity After Traumatic Brain Injury.

“The endocannabinoid (eCB) system helps recovery following traumatic brain injury (TBI).

Treatment with 2-arachidonoylglycerol (2-AG), a cerebral eCB ligand, was found to ameliorate the secondary damage.

Interestingly, the fatty acid amino acid amide (FAAA) N-arachidonoyl-L-serine (AraS) exerts similar eCB dependent neuroprotective. The present study aimed to investigate the effects of the FAAA palmitoyl-serine (PalmS) following TBI.

We suggest that the neuroprotective action of PalmS is mediated by indirect activation of the eCB receptors following TBI. One such mechanism may involve receptor palmitoylation which has been reported to result in structural stabilization of the receptors and to an increase in their activity. Further research is required in order to establish this assumption.”

http://www.ncbi.nlm.nih.gov/pubmed/25721934

http://www.thctotalhealthcare.com/category/brain-trauma/

Renal Effects of Chronic Pharmacological Manipulation of CB2 in Rats with Diet Induced Obesity.

“In diabetic nephropathy CB2 agonism reduces albuminuria and podocyte loss; however the role of CB2 in obesity-related nephropathy is unknown. The aim of this study was to determine the role of CB2 in a model of diet-induced obesity (DIO)…

This study demonstrates that while agonism of CB2 with AM1241 treatment for six weeks does not reduce weight gain in obese rats, it leads to improvements in obesity related renal dysfunction.”

http://www.ncbi.nlm.nih.gov/pubmed/25537025

Alexandros Makriyannis is a professor in the Department of Medicinal Chemistry at Northeastern University, where his research group has synthesized many new compounds with cannabinoid activity.

Chronic administration with AM251 improves albuminuria and renal tubular structure in obese rats.

“Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established, however the direct effects of CB1 antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB1 antagonist AM251 in a model of DIO.

Antagonism of CB1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats.

Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGF, TGFb1 and collagen IV in the kidney.

This study demonstrates that treatment with CB1 antagonist AM251 improves renal outcomes in obese rats.”

http://www.ncbi.nlm.nih.gov/pubmed/25804605

Alexandros Makriyannis is a professor in the Department of Medicinal Chemistry at Northeastern University, where his research group has synthesized many new compounds with cannabinoid activity… AM-251 — an inverse agonist at the CB1 cannabinoid receptor that is structurally related to SR141716A (rimonabant), but has a higher binding affinity with a Ki value of 7.5nM.”  http://en.wikipedia.org/wiki/List_of_AM_cannabinoids

Endocannabinoid transport revisited.

“Endocannabinoids are arachidonic acid-derived endogenous lipids that activate the endocannabinoid system which plays a major role in health and disease.

The primary endocannabinoids are anandamide (AEA, N-arachidonoylethanolamine) and 2-arachidonoyl glycerol.

While their biosynthesis and metabolism have been studied in detail, it remains unclear how endocannabinoids are transported across the cell membrane.

In this review, we critically discuss the different models of endocannabinoid trafficking, focusing on AEA cellular uptake which is best studied. The evolution of the current knowledge obtained with different AEA transport inhibitors is reviewed and the confusions caused by the lack of their specificity discussed.

A comparative summary of the most important AEA uptake inhibitors and the studies involving their use is provided. Based on a comprehensive literature analysis, we propose a model of facilitated AEA membrane transport followed by intracellular shuttling and sequestration.

We conclude that novel and more specific probes will be essential to identify the missing targets involved in endocannabinoid membrane transport.”

http://www.ncbi.nlm.nih.gov/pubmed/25817877

Elevation of Plasma 2-Arachidonoylglycerol Levels in Alzheimer’s Disease Patients as a Potential Protective Mechanism against Neurodegenerative Decline.

“Growing evidence suggests that the endocannabinoid system is involved in the pathogenesis of Alzheimer’s disease (AD) and atherosclerosis.

The purpose of this study was to investigate the activation of the endocannabinoid system in AD in vivo and the possible intermediate role of atherosclerosis…

AD patients present high plasma 2-AG levels, also in relation to heart ischemic disease and cerebral leukoaraiosis.

This may be a protective mechanism hindering neurodegeneration, but it may also play an ambivalent role on cerebrovascular circulation.

The increase in 2-AG and PEA levels observed with ongoing pathological processes may differently modulate cognitive performances.”

http://www.ncbi.nlm.nih.gov/pubmed/25818503

Endocannabinoid System

Wiley

“The endocannabinoid system (ECS) is defined as the signalling system composed of: (1) the two G‐protein‐coupled receptors known as cannabinoid receptors of type‐1 and ‐2 (CB1 and CB2); (2) the two most studied endogenous agonists of such receptors, the endocannabinoids anandamide (N‐arachidonoyl‐ethanolamine) and 2‐AG (2‐arachidonoyl‐glycerol); (3) enzymes and other proteins regulating the tissue levels of endocannabinoids; and (4) enzymes and other proteins that, together with endocannabinoids, regulate the activity of cannabinoid receptors.

A key role of the ECS is emerging in the control not only of central and peripheral nervous system functions, but also of most aspects of mammalian physiology, including energy intake, processing and storage, the immune response, reproduction and cell fate.

The ECS is also subject to dysregulation, and this seems to contribute to the symptoms and progress of several diseases. Hence, the possibility of developing new therapies starting from our increasing knowledge of the ECS is discussed.”

http://www.els.net/WileyCDA/ElsArticle/refId-a0023403.html

http://www.thctotalhealthcare.com/category/endocannabinoid-system/

Involvement of GluR2 up-regulation in neuroprotection by electroacupuncture pretreatment via cannabinoid CB1 receptor in mice.

“We investigated whether glutamate receptor subunit 2 (GluR2) is involved in EA pretreatment-induced neuroprotection via cannabinoid CB1 receptors (CB1R) after global cerebral ischemia in mice…

In conclusion, GluR2 up-regulation is involved in neuroprotection of EA pretreatment against GCI through CB1R, suggesting that GluR2 may be a novel target for stroke intervention.”

http://www.ncbi.nlm.nih.gov/pubmed/25830356

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

Interaction of cannabinoid receptor 2 and social environment modulates chronic alcohol consumption.

“Genetic and environmental factors contribute nearly with equal power to the development of alcoholism. Environmental factors, like negative life events or emotionally disruptive conditions initiate and promote alcohol drinking and relapse.

The endocannabinoid system is involved in hedonic control and modulates stress reactivity. Furthermore, chronic alcohol drinking alters endocannabinoid signalling, which in turn influences the stress reactivity.

Recently it has been shown that CB2 receptor activity influences stress sensitivity and alcohol drinking. We hypothesised that CB2 receptors influence the impact of environmental risk factors on alcohol preference and consumption. Therefore, in this study we investigated the alcohol-drinking pattern of wild type and CB2 deficient animals under single and group housing conditions using different alcohol drinking models, like forced drinking, intermittent forced drinking and two-bottle choice paradigms.

Our data showed that CB2 receptor modulates alcohol consumption and reward.

Interestingly, we detected that lack of CB2 receptors led to increased alcohol drinking in the intermittent forced drinking paradigm under group housing conditions.

Furthermore, we found that CB2 knockout mice consumed more food and that their body weight gain was modulated by social environment.

On the base of these data, we conclude that social environment critically affects the modulatory function of CB2 receptors especially in alcohol intake.

These findings suggest that a treatment strategy targeting CB2 receptors may have a beneficial effect on pathologic drinking particularly in situations of social stress and discomfort.”