“The endocannabinoid system is an endogenous signaling system that plays a role in the regulation of energy homeostasis and lipid and glucose metabolism-all of which can influence cardiometabolic risk. The endocannabinoid system appears to be a promising novel mechanistic pathway that modulates important aspects afcardiovascular and metabolic function. The endocannabinoid system is normally a silent physiologic system that becomes transiently activated, that is, only when needed. Evidence suggests that the endocannabinoid system is tonically overactive in human obesity and in animal models of genetic and diet-induced obesity. However, there is evidence in studies that the ECS is tonically overactivated in obesity, although it remains unclear whether overactivation of the ECS precedes or is consequent to expression of the obese phenotype. Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce smoking, body weight and improve and improves the profile of several metabolic risk factors in high-risk patients.”
Tag Archives: endocannabinoid system
Mitochondria: A Possible Nexus for the Regulation of Energy Homeostasis by the Endocannabinoid System?
“The endocannabinoid system (ECS) regulates numerous cellular and physiological processes through the activation of receptors targeted by endogenously produced ligands called endocannabinoids. Importantly, this signalling system is known to play an important role in modulating energy balance and glucose homeostasis. For example, current evidence indicates that the ECS becomes overactive during obesity whereby its central and peripheral stimulation drives metabolic processes that mimic the metabolic syndrome. Herein, we examine the role of the ECS in modulating the function of mitochondria which play a pivotal role in maintaining cellular and systemic energy homeostasis, in large part due to their ability to tightly coordinate glucose and lipid utilisation. Because of this, mitochondrial dysfunction is often associated with peripheral insulin resistance and glucose intolerance, as well as the manifestation of excess lipid accumulation in the obese state. This review aims to highlight the different ways through which the ECS may impact upon mitochondrial abundance and/or oxidative capacity, and where possible, relate these findings to obesity-induced perturbations in metabolic function. Furthermore, we explore the potential implications of these findings in terms of the pathogenesis of metabolic disorders and how these may be used to strategically develop therapies targeting the ECS.”
Towards a personalized treatment in depression: endocannabinoids, inflammation and stress response.
“The complex nature of depression is mirrored by difficulties in tailoring its treatment. Key underlying mechanisms of this mental disorder include elevated inflammation and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. More recently, the endocannabinoid system has been proposed as another important component in the pathogenesis of depression, and strong evidence suggests that all three systems communicate with each other. A growing number of genetic studies have investigated polymorphisms in depression in each of these systems separately. However, no study to date has looked at these genes in conjunction. In this article we will review the crosstalk between the endocannabinoid system, immune system and HPA axis; and discuss the evidence of gene polymorphisms and their relation to the risk of depression and its treatment. We propose future directions where genes of these three systems are considered from a joint perspective to improve prediction of treatment response, taking into account potentially overlooked genetic variations.”
Cannabinoid-induced autophagy regulates suppressor of cytokine signaling (SOCS)-3 in intestinal epithelium.
“Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associates impaired autophagy, increased activity in the endocannabinoid system and upregulation of suppressor of cytokine signaling (SOCS)-3 protein expression during intestinal inflammatory states. We have investigated whether these three processes are linked. By assessing the impact of phyto-cannabinoid cannabidiol (CBD), synthetic cannabinoid (ACEA) and endocannabinoid (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated CaCo2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid receptor (CB)-1 mediated. In contrast, CBD was able to bypass both the CB1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking both early and late autophagy. In conclusion, the regulatory protein, SOCS3, is itself regulated by autophagy and cannabinoids play a role in this process, which could be important when considering therapeutic applications for the cannabinoids in inflammatory conditions.”
New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.
“Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety.
The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients… New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system… emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives.”
http://www.ncbi.nlm.nih.gov/pubmed/24831882
http://www.thctotalhealthcare.com/category/fragile-x-syndrome-fxs/
Functionalization of β-Caryophyllene Generates Novel Polypharmacology in the Endocannabinoid System.
“The widespread dietary plant sesquiterpene hydrocarbon β-caryophyllene is a CB2 cannabinoid receptor-specific agonist showing anti-inflammatory and analgesic effects in vivo…
Our study shows that by removing the conformational constraints induced by the medium-sized ring and by introducing functional groups in the sesquiterpene hydrocarbon 1, a new scaffold with pronounced polypharmacological features within the endocannabinoid system could be generated.
The structural and functional repertoire of cannabimimetics and their yet poorly understood intrinsic promiscuity may be exploited to generate novel probes and ultimately more effective drugs.”
http://www.ncbi.nlm.nih.gov/pubmed/24831513
“Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception…β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis… The combined injection of morphine and BCP may be an alternative in treating chemogenic pain.” http://www.ncbi.nlm.nih.gov/pubmed/23138934
Novel approaches to the development of anti-sepsis drugs.
“Sepsis is the dysregulated systemic immune response to an infection…
The authors discuss specific pharmacological approaches with a focus on immune modulation, for example, Toll-like receptor 4 inhibition and modulation of the endocannabinoid system.”
Experimental cannabinoid 2 receptor-mediated immune modulation in sepsis.
“Sepsis is a complex condition that results from a dysregulated immune system in response to a systemic infection. Current treatments lack effectiveness in reducing the incidence and mortality associated with this disease. The endocannabinoid system offers great promise in managing sepsis pathogenesis due to its unique characteristics.
The present study explored the effect of modulating the CB2 receptor pathway in an acute sepsis mouse model.
Using various compounds we have shown different mechanisms of activating CB2 receptors to reduce leukocyte endothelial interactions in order to prevent further inflammatory damage during sepsis.”
Getting High on the Endocannabinoid System
“The endogenous cannabinoid system—named for the plant that led to its discovery—is one of the most important physiologic systems involved in establishing and maintaining human health.
Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind.
By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.
…either stimulating or inhibiting the endocannabinoid system could have beneficial effects.
The most direct route of THC administration is by smoking marijuana or other forms of cannabis. Yet purified, FDA-approved medicinal preparations of THC are available in pill form… Why not just take a pill? There are several reasons that some patients prefer puffing over swallowing. One quantitatively minor factor is potential lethality.
It is possible to get a fatal overdose by swallowing too many THC pills at once, whereas documented evidence of death simply from smoking too much cannabis does not seem to exist.”
Anandamide Attenuates Th-17 Cell-Mediated Delayed-Type Hypersensitivity Response by Triggering IL-10 Production and Consequent microRNA Induction
“Endogenous cannabinoids [endocannabinoids] are lipid signaling molecules that have been shown to modulate immune functions..
Cannabinoids are compounds derived from the Cannabis sativa plant and exert many effects on the immune system. Cannabinoids have potential as therapeutic agents in several different disease conditions, including experimental autoimmune hepatitis, Multiple Sclerosis, and Graft vs. Host Disease…
This report suggested a role of the endogenous cannabinoid system in regulation of allergic inflammation.
These studies also suggest that endogenous cannabinoid system is one of the homeostatic mechanisms that the body employs to down-regulate immune response to foreign antigens as well as combat autoimmunity.
Targeting of this system could yield valuable therapeutics in the future.”
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0093954