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/

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.”

Differential effect of cannabinol and cannabidiol on THC-induced responses during abstinence in morphine-dependent rats.

“The same dose of cannabinol (CBN) or cannabidiol (CBD) further increased the attenuation of precipitated abstinence signs observed in morphine-dependent rats that also received an acute dose of delta 9-THC. By contrast, rotational behavior (turning), which is observed concomitantly in THC-treated rats during morphine abstinence, was not increased by CBN, but was potentiated by CBD.

These data illustrate differences between psychoinactive cannabinoids in their interaction with delta 9-THC that might be relevant to possible clinical use of Cannabis in narcotic detoxification.”

Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing.

“An immunomodulatory role for the endocannabinoid system in gastrointestinal inflammatory disorders has been proposed and this study sought to determine the location of both cannabinoid receptors in human colon and to investigate epithelial receptor function.

The location of CB1 and CB2 receptors in human colonic tissue was determined by immunohistochemistry…

Cannabinoids enhanced epithelial wound closure…

CONCLUSIONS:

CB1 receptors are expressed in normal human colon and colonic epithelium is responsive biochemically and functionally to cannabinoids. Increased epithelial CB2-receptor expression in human inflammatory bowel disease tissue implies an immunomodulatory role that may impact on mucosal immunity.”

http://www.ncbi.nlm.nih.gov/pubmed/16083701

Cannabinoid receptor type 2 is time-dependently expressed during skin wound healing in mice.

“Dynamic localization of CB2R and quantitative analysis of CB2R mRNA during skin wound healing in mice were performed…

In conclusion, dynamic distribution and expression of CB2R suggest that CB2R is involved in modulating macrophages and myofibroblasts in response to inflammatory event and repair process in mouse skin wound healing, and CB2R is available as a marker for wound age determination.”

http://www.ncbi.nlm.nih.gov/pubmed/22814434

The cannabinoid receptor type 2 is time-dependently expressed during skeletal muscle wound healing in rats.

“The expression of the cannabinoid receptor type 2 (CB2R) was investigated by immunohistochemistry, Western blotting, and RT-PCR during wound healing of contused skeletal muscle in rats with attempt of its applicability to skeletal muscle wound age estimation…

In conclusion, dynamic distribution and expression of CB2R suggest that CB2R be involved in modulating macrophages in response to inflammatory event in rat skeletal muscle wound healing and CB2R be available as a marker for wound age determination.”

[Expression of cannabinoid receptor I during mice skin incised wound healing course].

“To investigate the expression of cannabinoid receptor I (CB1R) during mice skin incised wound healing course and time-dependent changes of CB1R in wound age determination…

The control group showed a low expression of CB1R detected mainly in epidermis, hair follicles, sebaceous gland and dermomuscular layer. CB1R expression was undetectable in neutrophils in the wound specimens from 6h to 12h post-injury.

The positive bands of CB1R were observed in all time points of the wound healing course…

CONCLUSION:

CB1R is activated during the wound healing course. The expression of CB1R is found in mononuclear cells, which could be involved in inflammation reaction. CBIR is observed in fibroblastic cells, which could participate in the wound healing. CB1R may be a potentially useful marker for determination of wound healing age.”

http://www.ncbi.nlm.nih.gov/pubmed/20967946