Perinatal maternal high-fat diet induces early obesity and sex-specific alterations of the endocannabinoid system in white and brown adipose tissue of weanling rat offspring.

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“Perinatal maternal high-fat (HF) diet programmes offspring obesity. Obesity is associated with overactivation of the endocannabinoid system (ECS) in adult subjects, but the role of the ECS in the developmental origins of obesity is mostly unknown. The ECS consists of endocannabinoids, cannabinoid receptors (cannabinoid type-1 receptor (CB1) and cannabinoid type-2 receptor (CB2)) and metabolising enzymes.

We hypothesised that perinatal maternal HF diet would alter the ECS in a sex-dependent manner in white and brown adipose tissue of rat offspring at weaning in parallel to obesity development.

Maternal HF diet induced early obesity, white adipocyte hypertrophy and increased lipid accumulation in brown adipose tissue associated with sex-specific changes of the ECS’s components in weanling rats. In male pups, maternal HF diet decreased CB1 and CB2 protein in subcutaneous adipose tissue. In female pups, maternal HF diet increased visceral and decreased subcutaneous CB1. In brown adipose tissue, maternal HF diet increased CB1 regardless of pup sex. In addition, maternal HF diet differentially changed oestrogen receptor across the adipose depots in male and female pups.

The ECS and oestrogen signalling play an important role in lipogenesis, adipogenesis and thermogenesis, and we observed early changes in their targets in adipose depots of the offspring. The present findings provide insights into the involvement of the ECS in the developmental origins of metabolic disease induced by inadequate maternal nutrition in early life.”

https://www.ncbi.nlm.nih.gov/pubmed/29110748

https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/perinatal-maternal-highfat-diet-induces-early-obesity-and-sexspecific-alterations-of-the-endocannabinoid-system-in-white-and-brown-adipose-tissue-of-weanling-rat-offspring/6BA3A77DE45A1537E0BC182E83EF07F0

Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study.

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“Cannabis-based drugs have been shown to be effective in inflammatory diseases.

A number of endocannabinoids including N- arachidonoylethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) with activity at the cannabinoidreceptors (CBR) CBR1 and CBR2, have been identified. Other structurally related endogenous fatty acid compounds such as oleoylethanolamide (OEA) and palmitoyl ethanolamide (PEA) have been identified in biological tissues.

These compounds do not bind to CBR but might be involved in facilitating the actions of directly acting endocannabinoids and thus are commonly termed “entourage” compounds due to their ability to modulate the endocannabinoid system.

The aim of this study was to evaluate the presence of endocannabinoids and entourage compounds in the synovial fluid of dogs with osteoarthritis subjected to arthrotomy of the knee joint. Cytokines and cytology were studied as well.

AEA, 2-AG, OEA and PEA were all present in the synovial fluid of arthritic knees and in the contralateral joints; in addition, a significant increase of OEA and 2AG levels were noted in SF from OA knees when compared to the contralateral joints.

The identification and quantification of endocannabinoids and entourage compounds levels in synovial fluids from dogs with OA of the knee is reported for the first time. Our data are instrumental for future studies involving a greater number of dogs. Cannabinoids represent an emerging and innovative pharmacological tool for the treatment of OA and further studies are warranted to evaluate the effectiveness of cannabinoids in veterinary medicine.”

https://www.ncbi.nlm.nih.gov/pubmed/29110674

“The ECS can be exploited as a potential therapeutic option for OA. We have demonstrated the presence of AEA, 2-AG, OEA and PEA in the SF of dogs with OA. Our data open the avenue to future studies involving a higher number of dogs and aimed at defining the role played by these compounds in OA of the dogs. Both plant-derived and synthetic agonists of CBRs represent an emerging and innovative pharmacological tool for the treatment of OA. ” https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-017-1245-7

Cannabinoid receptor 1/2 double-knockout mice develop epilepsy.

Epilepsia

“The endocannabinoid system has gained attention as an important modulator of activity in the central nervous system. Initial studies focused on cannabinoid receptor 1 (CB1), which is widely expressed in the brain, but recent work also implicates cannabinoidreceptor 2 (CB2) in modulating neuronal activity.

Both receptors are capable of reducing neuronal activity, generating interest in cannabinoid receptor agonists as potential anticonvulsants.

CB1 (Cnr1) and CB2 (Cnr2) single-knockout mice have been generated, with the former showing heightened seizure sensitivity, but not overt seizures. Given overlapping and complementary functions of CB1 and CB2 receptors, we queried whether double-knockout mice would show an exacerbated neurological phenotype.

Strikingly, 30% of double-knockout mice exhibited provoked behavioral seizures, and 80% were found to be epileptic following 24/7 video-electroencephalographic monitoring. Single-knockout animals did not exhibit seizures. These findings highlight the importance of the endocannabinoid system for maintaining network stability.”

https://www.ncbi.nlm.nih.gov/pubmed/29105060

http://onlinelibrary.wiley.com/doi/10.1111/epi.13930/abstract

The Endocannabinoid System Differentially Regulates Escape Behavior in Mice.

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“Among the hardwired behaviors, fear or survival responses certainly belong to the most evolutionary conserved ones. However, higher animals possess the ability to adapt to certain environments (e.g., novel foraging grounds), and, therefore, those responses need to be plastic. Previous studies revealed a cell-type specific role of the endocannabinoid system in novelty fear, conditioned fear and active vs. passive avoidance in a shuttle box paradigm.

In this study we aim to investigate, whether knocking-out the cannabinoidreceptor type-1 (CB1) on cortical glutamatergic (Glu-CB1-/-) or GABAergic (GABA-CB1-/-) neurons differentially affects the level of behavioral inhibition, which could ultimately lead to differences in escape behavior.

Taken together, we could show that CB1 on cortical glutamatergic terminals is important for the acquisition of active avoidance, as the absence of CB1 on these neurons creates a bias toward inhibitory avoidance. This is the case in situations without punishment such as electric footshocks. On the contrary CB1 receptors on GABAergic neurons mediate the acquisition of passive avoidance, as the absence of CB1 on those neurons establishes a strong bias toward escape behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/29104536

https://www.frontiersin.org/articles/10.3389/fnbeh.2017.00201/full

Parameters of the Endocannabinoid System as Novel Biomarkers in Sepsis and Septic Shock.

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“Sepsis represents a dysregulated immune response to infection, with a continuum of severity progressing to septic shock. This dysregulated response generally follows a pattern by which an initial hyperinflammatory phase is followed by a state of sepsis-associated immunosuppression.

Major challenges in improving sepsis care include developing strategies to ensure early and accurate identification and diagnosis of the disease process, improving our ability to predict outcomes and stratify patients, and the need for novel sepsis-specific treatments such as immunomodulation.

Biomarkers offer promise with all three of these challenges and are likely also to be the solution to determining a patient’s immune status; something that is critical in guiding effective and safe immunomodulatory therapy. Currently available biomarkers used in sepsis lack sensitivity and specificity, among other significant shortcomings.

The endocannabinoid system (ECS) is an emerging topic of research with evidence suggesting a ubiquitous presence on both central and peripheral tissues, including an intrinsic link with immune function. This review will first discuss the state of sepsis biomarkers and lack of available treatments, followed by an introduction to the ECS and a discussion of its potential to provide novel biomarkers and treatments.”

https://www.ncbi.nlm.nih.gov/pubmed/29104224

http://www.mdpi.com/2218-1989/7/4/55

Maternal high-fat diet induces sex-specific endocannabinoid system changes in newborn rats and programs adiposity, energy expenditure and food preference in adulthood.

The Journal of Nutritional Biochemistry

“Early life inadequate nutrition triggers developmental adaptations and adult chronic disease.

Maternal high-fat (HF) diet promotes visceral obesity and hypothalamic leptin resistance in male rat offspring at weaning and adulthood.

Obesity is related to over active endocannabinoid system (ECS). The ECS consists mainly of endogenous ligands, cannabinoid receptors (CB1 and CB2), and the enzymes fatty acid anandamide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

We hypothesized that perinatal maternal HF diet would regulate offspring ECS in hypothalamus and brown adipose tissue (BAT) at birth, prior to visceral obesity development, and program food preference and energy expenditure of adult offspring.

In conclusion, maternal HF diet alters ECS components and energy metabolism targets in hypothalamus and BAT of offspring at birth, in a sex-specific manner, which may contribute for hyperphagia, food preference and higher adiposity later in life.”

https://www.ncbi.nlm.nih.gov/pubmed/29102876

http://www.sciencedirect.com/science/article/pii/S0955286317303042?via%3Dihub

Translating Endocannabinoid Biology into Clinical Practice: Cannabidiol for Stroke Prevention.

Mary Ann Liebert, Inc. publishers

“Introduction: The endocannabinoid system (ECS) regulates functions throughout human physiology, including neuropsychiatric, cardiovascular, autonomic, metabolic, and inflammatory states. The complex cellular interactions regulated by the ECS suggest a potential for vascular disease and stroke prevention by augmenting central nervous and immune cell endocannabinoid signaling.

Discussion: The endocannabinoid N-arachidonoylethanolamine (anandamide) plays a central role in augmenting these processes in cerebrovascular and neurometabolic disease. Furthermore, cannabidiol (CBD), a nonpsychoactive constituent of Cannabis, is an immediate therapeutic candidate both for potentiating endocannabinoid signaling and for acting at multiple pharmacological targets.

Conclusion: This speculative synthesis explores the current state of knowledge of the ECS and suggests CBD as a therapeutic candidate for stroke prevention by exerting favorable augmentation of the homeostatic effects of the ECS and, in turn, improving the metabolic syndrome, while simultaneously stalling the development of atherosclerosis.”

Review: The Role of Cannabinoids on Esophageal Function-What We Know Thus Far.

Mary Ann Liebert, Inc. publishers

“The endocannabinoid system (ECS) primarily consists of cannabinoid receptors (CBRs), endogenous ligands, and enzymes for endocannabinoid biosynthesis and inactivation. Although the presence of CBRs, both CB1 and CB2, as well as a third receptor (G-protein receptor 55 [GPR55]), has been established in the gastrointestinal (GI) tract, few studies have focused on the role of cannabinoids on esophageal function. To date, studies have shown their effect on GI motility, inflammation and immunity, intestinal and gastric acid secretion, nociception and emesis pathways, and appetite control. Given the varying and sometimes limited efficacy of current medical therapies for diseases of the esophagus, further understanding and investigation into the interplay of the ECS on esophageal health and disease may present new therapeutic modalities that may help advance current treatment options. In this brief review, the current understanding of the ECS role in various esophageal functions and disorders is presented.”

https://www.ncbi.nlm.nih.gov/pubmed/29098187

http://online.liebertpub.com/doi/10.1089/can.2017.0031

The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: clues for other neuroinflammatory diseases.

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“Multiple sclerosis is the most common inflammatory demyelinating disease of the central nervous system, caused by an autoimmune response against myelin that eventually leads to progressive neurodegeneration and disability. Although the knowledge on its underlying neurobiological mechanisms has considerably improved, there is a still unmet need for new treatment options, especially for the progressive forms of the disease.

Both preclinical and clinical data suggest that cannabinoids, derived from the Cannabis sativa plant, may be used to control symptoms such as spasticity and chronic pain, whereas only preclinical data indicate that these compounds and their endogenous counterparts, i.e. the endocannabinoids, may also exert neuroprotective effects and slow down disease progression.

Here, we review the preclinical and clinical studies that could explain the therapeutic action of cannabinoid-based medicines, as well as the medical potential of modulating endocannabinoid signaling in multiple sclerosis, with a link to other neuroinflammatory disorders that share common hallmarks and pathogenetic features.”

https://www.ncbi.nlm.nih.gov/pubmed/29097192

http://www.sciencedirect.com/science/article/pii/S0301008217300709

THC inhibits the expression of ethanol-induced locomotor sensitization in mice.

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“The motivational circuit activated by ethanol leads to behavioral changes that recruit the endocannabinoid system (ECS). Case reports and observational studies suggest that the use of Cannabis sp. mitigates problematic ethanol consumption in humans.

Here, we verified the effects of the two main phytocannabinoid compounds of Cannabis sp., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), in the expression of ethanol-induced locomotor sensitization in mice.

Our findings showing that phytocannabinoid treatment prevents the expression of behavioral sensitization in mice provide insight into the potential therapeutic use of phytocannabinoids in alcohol-related problems.”

https://www.ncbi.nlm.nih.gov/pubmed/29084627

http://www.sciencedirect.com/science/article/pii/S0741832916302877?via%3Dihub