Changes in the Peripheral Endocannabinoid System as a Risk Factor for the Development of Eating Disorders.

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“Eating Disorder (ED) is characterized by persistently and severely disturbed eating behaviours. They arise from a combination of long-standing behavioural, emotional, psychological, interpersonal, and social factors and result in insufficient nutrient ingestion and/or adsorption. The three main EDs are: anorexia nervosa, bulimia nervosa, and binge eating disorder. We review the role of peripheral endocannabinoids in eating behaviour.

DISCUSSION:

The neuronal pathways involved in feeding behaviours are closely related to catecholaminergic, serotoninergic and peptidergic systems. Accordingly, feeding is promoted by serotonin, dopamine, and prostaglandin and inhibited by neuropeptide Y, norepinephrine, GABA, and opioid peptides. The endocannabinoid system plays a role in EDs, and multiple lines of evidence indicate that the cannabinoid signalling system is a key modulatory factor of the activity in the brain areas involved in EDs as well as in reward processes.

CONCLUSION:

Besides their central role in controlling food behaviours, peripheral cannabinoids are also involved in regulating adipose tissue and insulin signalling as well as cell metabolism in peripheral tissues such as liver, pancreas, fatty tissue, and skeletal muscle. Altogether, these data indicate that peripheral cannabinoids can provide new therapeutic targets not only for EDs but also for metabolic disease.”

https://www.ncbi.nlm.nih.gov/pubmed/29437028

Long-term depression induced by endogenous cannabinoids produces neuroprotection via astroglial CB1R after stroke in rodents.

 SAGE Journals

“Ischemia not only activates cell death pathways but also triggers endogenous protective mechanisms. However, it is largely unknown what is the essence of the endogenous neuroprotective mechanisms induced by preconditioning. In this study we demonstrated that systemic injection of JZL195, a selective inhibitor of eCB clearance enzymes, induces in vivo long-term depression at CA3-CA1 synapses and at PrL-NAc synapses produces neuroprotection. JZL195-elicited long-term depression is blocked by AM281, the antagonist of cannabinoid 1 receptor (CB1R) and is abolished in mice lacking cannabinoid CB1 receptor (CB1R) in astroglial cells, but is conserved in mice lacking CB1R in glutamatergic or GABAergic neurons. Blocking the glutamate NMDA receptor and the synaptic trafficking of glutamate AMPA receptor abolishes both long-term depression and neuroprotection induced by JZL195. Mice lacking CB1R in astroglia show decreased neuronal death following cerebral ischemia. Thus, an acute elevation of extracellular eCB following eCB clearance inhibition results in neuroprotection through long-term depression induction after sequential activation of astroglial CB1R and postsynaptic glutamate receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/29432698

http://journals.sagepub.com/doi/abs/10.1177/0271678X18755661?journalCode=jcba

Endocannabinoid system and cannabinoids in neurogenesis – new opportunities for neurological treatment? Reports from experimental studies.

“Neurogenesis is one of the most important phenomenona affecting human life. This process consists of proliferation, migration and differentiation of neuroblasts and synaptic integrations of newborn neurons.
Proliferation of new cells continues into old age, also in humans, although the most extensive process of cell formation occurs during the prenatal period. It is possible to distinguish two regions in the brain responsible for neurogenesis: the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ). Hippocampal neurogenesis is very sensitive to various physiological and pathological stimuli.
The functional integration of the newly-born dentate granule cells into hippocampal circuitry, and their ability to mediate long-term potentiation in DG, has led to the hypothesis that neurogenesis in the adult brain may play a key role in learning and memory function, as well as cognitive dysfunction in some diseases.
Brain disorders, such as neurodegenerative diseases or traumatic brain injuries, significantly affect migration, proliferation and differentiation of neural cells. In searching for the best neurological drugs protecting neuronal cells, stimulating neurogenesis, while also developing no side-effects, endocannabinoids proved to be a strong group of substances having many beneficial properties.
Therefore, the latest data is reviewed of the various experimental studies concerning the analysis of the most commonly studied cannabinoids and their impact on neurogenesis.”

The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2.

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“Decades of research has provided evidence for the role of the endocannabinoid system in human health and disease. This versatile system, consisting of two receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and metabolic enzymes has been implicated in a wide variety of disease states, ranging from neurological disorders to cancer.

CB2 has gained much interest for its beneficial immunomodulatory role that can be obtained without eliciting psychotropic effects through CB1. Recent studies have shed light on a protective role of CB2 in cardiovascular disease, an ailment which currently takes more lives each year in Western countries than any other disease or injury.

By use of CB2 knockout mice and CB2-selective ligands, knowledge of how CB2 signaling affects atherosclerosis and ischemia has been acquired, providing a major stepping stone between basic science and translational clinical research.

Here, we summarize the current understanding of the endocannabinoid system in human pathologies and provide a review of the results from preclinical studies examining its function in cardiovascular disease, with a particular emphasis on possible CB2-targeted therapeutic interventions to alleviate atherosclerosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29412125

“Researchers suggest that THC and other cannabinoids, which are active at CB2, the cannabinoid receptor expressed on immune cells, may be valuable in treating atherosclerosis.” https://www.medscape.com/viewarticle/787468

“Cardiovascular disease: New use for cannabinoids”  https://www.nature.com/articles/nrd1733

The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

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“Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS).

Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines.

Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans.

The present study revealed an upregulated endocannabinoid system in dogs with inflammatory CNS diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29408878

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187197

Cannabinoid Receptors in Diabetic Kidney Disease.

 Current Diabetes Reports

“The purpose of this review is to examine and summarize studies assessing the relevance of the endocannabinoid system (ECS) in diabetic kidney disease (DKD).

Endocannabinoids and endocannabinoid receptors of type 1 (CB1R) and of type 2 (CB2R) are present in the normal kidney. Expression of CB1R and CB2R is altered in experimental DKD.

Studies in experimental animals and cultured kidney cells show a beneficial effect of peripheral CB1R blockade and CB2R activation in DKD and an even greater efficacy of a combined treatment.

Preclinical studies confirm that both CB1R and CB2R are implicated in the pathogenesis of DKD and may represent novel targets for treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/29399721

Targeting the endocannabinoid system as a potential anticancer approach.

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“The endocannabinoid system is currently under intense investigation due to the therapeutic potential of cannabinoid-based drugs as treatment options for a broad variety of diseases including cancer.

Besides the canonical endocannabinoid system that includes the cannabinoid receptors CB1 and CB2 and the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, recent investigations suggest that other fatty acid derivatives, receptors, enzymes, and lipid transporters likewise orchestrate this system as components of the endocannabinoid system when defined as an extended signaling network.

As such, fatty acids acting at cannabinoid receptors (e.g. 2-arachidonoyl glyceryl ether [noladin ether], N-arachidonoyldopamine) as well as endocannabinoid-like substances that do not elicit cannabinoid receptor activation (e.g. N-palmitoylethanolamine, N-oleoylethanolamine) have raised interest as anticancerogenic substances.

Furthermore, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid binding protein family, additional cannabinoid-activated G protein-coupled receptors, members of the transient receptor potential family as well as peroxisome proliferator-activated receptors have been considered as targets of antitumoral cannabinoid activity. Therefore, this review focused on the antitumorigenic effects induced upon modulation of this extended endocannabinoid network.” https://www.ncbi.nlm.nih.gov/pubmed/29390896  http://www.tandfonline.com/doi/abs/10.1080/03602532.2018.1428344?journalCode=idmr20

“Anticancer mechanisms of cannabinoids”   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/
“Cannabinoids as Anticancer Drugs.”

Analysis of endocannabinoid receptors and enzymes in the post-mortem motor cortex and spinal cord of amyotrophic lateral sclerosis patients.

Publication Cover

“We have investigated the endocannabinoid system in the motor cortex of motor neuron disease (MND) patients.

CONCLUSION:

We have confirmed that CB2 receptors are elevated in the motor cortex of MND patients associated with the reactive gliosis. This phenomenon is previous to neuronal losses. We also found CB2 receptors in cortical and spinal motor neurons.

These observations support that targeting this receptor may serve for developing neuroprotective therapies in MNDs.”

https://www.ncbi.nlm.nih.gov/pubmed/29334787

http://www.tandfonline.com/doi/abs/10.1080/21678421.2018.1425454?journalCode=iafd20

The therapeutic potential of targeting the peripheral endocannabinoid/CB1 receptor system.

European Journal of Internal Medicine

“Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CB1R and CB2R, respectively), which also mediate the different physiological effects of marijuana. The endocannabinoid system, consisting of eCBs, their receptors, and the enzymes involved in their biosynthesis and degradation, is present in a vast number of peripheral organs. In this review we describe the role of the eCB/CB1R system in modulating the metabolism in several peripheral organs. We assess how eCBs, via activating the CB1R, contribute to obesity and regulate food intake. In addition, we describe their roles in modulating liver and kidney functions, as well as bone remodeling and mass. Special importance is given to emphasizing the efficacy of the recently developed peripherally restricted CB1R antagonists, which were pre-clinically tested in the management of energy homeostasis, and in ameliorating both obesity- and diabetes-induced metabolic complications.”

https://www.ncbi.nlm.nih.gov/pubmed/29336868

Cannabinoid Modulation of the Stressed Hippocampus.

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“Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder and Schizophrenia.

The hippocampal formation is a forebrain structure highly associated with emotional, learning and memory processes; being particularly vulnerable to stress. Exposure to stressful stimuli leads to neuroplastic changes and imbalance between inhibitory/excitatory networks. These changes have been associated with an impaired hippocampal function.

Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus.

Cannabinoids receptors are highly expressed in the hippocampus, and several lines of evidence suggest that facilitation of cannabinoid signaling within this brain region prevents stress-induced behavioral changes.

Also, chronic stress modulates hippocampal CB1 receptors expression and endocannabinoid levels.

Moreover, cannabinoids participate in mechanisms related to synaptic plasticity and adult neurogenesis. Here, we discussed the main findings supporting the involvement of hippocampal cannabinoid neurotransmission in stress-induced behavioral and neuroplastic changes.”

https://www.ncbi.nlm.nih.gov/pubmed/29311804

https://www.frontiersin.org/articles/10.3389/fnmol.2017.00411/full