Category Archives: Endocannabinoid System

The novel peripherally active cannabinoid type 1 and serotonin type 3 receptor agonist AM9405 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome.

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European Journal of Pharmacology

“The endocannabinoid system (ECS) plays a crucial role in numerous physiological processes in the central and peripheral nervous systems. In the gastrointestinal (GI) tract, selective cannabinoid (CB) receptor agonists exert potent inhibitory actions on motility and pain signalling. In the present study, we used mouse models of diarrhea, hypermotility, and abdominal pain to examine whether a novel synthetic CB1 receptor agonist AM9405 [(2-(2,6-dihydroxy-4-(2-methyloctan-2-yl)phenyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-ium bromide); also known as GAT379] exhibits effects of potential therapeutic relevance. AM9405 significantly slowed mouse intestinal motility in physiological conditions. Moreover, AM9405 reversed hypermotility and reduced pain in mouse models mimicking symptoms of functional GI disorders, such as stress-induced diarrhoea and writhing test. Interestingly, some of the effects of AM9405 were blocked by a 5-HT3 antagonist suggesting interaction with 5-HT3 receptors. In our study we show that combining CB1 agonism with 5-HT3 agonism may alter physiological functions and experimental pathophysiologies in a manner that make such compounds promising drugs for the future treatment of functional GI disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/30121173

https://www.sciencedirect.com/science/article/pii/S0014299918304734?via%3Dihub

New approaches and challenges to targeting the endocannabinoid system.

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“The endocannabinoid signalling system was discovered because receptors in this system are the targets of compounds present in psychotropic preparations of Cannabis sativa. The search for new therapeutics that target endocannabinoid signalling is both challenging and potentially rewarding, as endocannabinoids are implicated in numerous physiological and pathological processes. Hundreds of mediators chemically related to the endocannabinoids, often with similar metabolic pathways but different targets, have complicated the development of inhibitors of endocannabinoid metabolic enzymes but have also stimulated the rational design of multi-target drugs. Meanwhile, drugs based on botanical cannabinoids have come to the clinical forefront, synthetic agonists designed to bind cannabinoid receptor 1 with very high affinity have become a societal threat and the gut microbiome has been found to signal in part through the endocannabinoid network. The current development of drugs that alter endocannabinoid signalling and how this complex system could be pharmacologically manipulated in the future are described in this Opinion article.”

https://www.ncbi.nlm.nih.gov/pubmed/30116049
https://www.nature.com/articles/nrd.2018.115

Cannabinoid signalling in the immature brain: encephalopathies and neurodevelopmental disorders.

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Biochemical Pharmacology

“The endocannabinoid system exerts a crucial neuromodulatory role in many brain areas that is essential for proper regulation of neuronal activity. The role of cannabinoid signalling controlling neuronal activity in the adult brain is also evident when considering its contribution to adult brain insults or neurodegenerative diseases.

In the context of brain genetic or acquired encephalopathies administration of cannabinoid-based molecules has demonstrated to exert symptomatic relief and hence, they are proposed as new potential therapeutic compounds.

This review article summarizes the main evidences indicating the beneficial action of cannabinoid-derived molecules in preclinical models of neonatal hypoxia/ischemic damage. In a second part, we discuss the available evidences of therapeutic actions of cannabidiol in children with refractory epilepsy syndromes. Finally, we discuss the current view of cannabinoid signalling mechanisms active in the immature brain that affect in neural cell fate and can contribute to long-term neural cell plasticity.”

https://www.ncbi.nlm.nih.gov/pubmed/30118663

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303344

Traditional Uses of Cannabinoids and New Perspectives in the Treatment of Multiple Sclerosis.

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“Recent findings highlight the emerging role of the endocannabinoid system in the control of symptoms and disease progression in multiple sclerosis (MS). MS is a chronic, immune-mediated, demyelinating disorder of the central nervous system with no cure so far. It is widely reported in the literature that cannabinoids might be used to control MS symptoms and that they also might exert neuroprotective effects and slow down disease progression. This review aims to give an overview of the principal cannabinoids(synthetic and endogenous) used for the symptomatic amelioration of MS and their beneficial outcomes, providing new potentially possible perspectives for the treatment of this disease.”

https://www.ncbi.nlm.nih.gov/pubmed/30111755

http://www.mdpi.com/2305-6320/5/3/91

Acute inflammation: endogenous cannabinoids mellow the harsh proinflammatory environment.

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“Under normal conditions, there is a paucity of neutrophils within the intestinal mucosa; however, these innate immune cells rapidly infiltrate the mucosa in response to infection and are critical for pathogen control. Unfortunately, these cells can cause extensive damage to the intestine if the initial inflammatory influx is not resolved. Factors that promote resolution of inflammation are of great interest, as they have therapeutic potential for limiting uncontrolled inflammatory damage. In this issue of the JCI, Szabady et al. demonstrate that the multidrug resistance transporter P-glycoprotein (P-gp) secretes endocannabinoids into the intestinal lumen that counteract the proinflammatory actions of the eicosanoid hepoxilin A3, which is secreted into the lumen by the efflux pump MRP2 and serves as a potent neutrophil chemoattractant. Moreover, the antiinflammatory actions of P-gp-secreted endocannabinoids were mediated by peripheral cannabinoid receptor CB2 on neutrophils. Together, the results of this study identify an important mechanism by which endogenous endocannabinoids facilitate the resolution of inflammation; this mechanism has potential to be therapeutically exploited.”

 https://www.ncbi.nlm.nih.gov/pubmed/30102253
https://www.jci.org/articles/view/122885
“Cannabinoids as novel anti-inflammatory drugs” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis.

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“Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen. Knockdown or inhibition of P-gp reduced luminal secretion levels of N-acyl ethanolamine-type endocannabinoids, which correlated with increased neutrophil transmigration in vitro and in vivo. Additionally, loss of CB2, the peripheral cannabinoid receptor, led to increased pathology and neutrophil influx in models of acute intestinal inflammation. These results define a key role for epithelial cells in balancing the constitutive secretion of antiinflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine.”

https://www.ncbi.nlm.nih.gov/pubmed/30102254

https://www.jci.org/articles/view/96817

Glial Endocannabinoid System in Pain Modulation.

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“Pain is affecting the human for centuries and there still is no satisfactory strategy for patients suffering pain particularly chronic pain although intensive studies about its mechanism have been performed in order to improve the treatment of pain.

Cannabinoid is a group of chemicals extracted from plants and has a long history in treating pain through the endogenous cannabinoid receptor in the body, however, its application in pain treatment is limited due to its inverse effects.

Recent studies have indicated that glial cells play critical role in mediating pain processing through multiple pathway, including excitatory and inhibitory neurotransmission in different levels of the nervous system.

Furthermore, the glial cells are found to express cannabinoid receptors.

This review summarized the recent studies about the cannabinoid system in glial cells, which may provide some insight for the studying of pain.”

https://www.ncbi.nlm.nih.gov/pubmed/30084280

https://www.tandfonline.com/doi/abs/10.1080/00207454.2018.1503178

Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.

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Kidney International Home

“The cannabinoid receptor type 2 (CB2) is a G protein-coupled seven transmembrane receptor that transmits endogenous cannabinoid signaling. The role of CB2 in the pathogenesis of kidney injury and fibrosis remains poorly understood.

Here we demonstrate that CB2 was induced, predominantly in kidney tubular epithelium, in various models of kidney disease induced by unilateral ureteral obstruction, adriamycin or ischemia/reperfusion injury.

By using in silico screening and medicinal chemistry modifications, we discovered a novel compound, XL-001, that bound to CB2 with high affinity and selectivity and acted as an inverse agonist. Delayed administration of XL-001 was also effective in ameliorating kidney fibrosis and inflammation.

Thus, CB2 is a pathogenic mediator in kidney fibrosis and targeted inhibition with the novel inverse agonist XL-001 may provide a strategy in the fight against fibrotic kidney diseases.”

 https://www.ncbi.nlm.nih.gov/pubmed/30093080
https://www.kidney-international.org/article/S0085-2538(18)30397-1/fulltext

Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model.

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Biochemical Pharmacology

“Activating CB1 cannabinoid receptor has been demonstrated to produce certain therapeutic effects in animal models of Alzheimer’s disease (AD).

In this study, we evaluated the specific contribution of CB1 receptor to the progression of AD-like pathology in double transgenic APP/PS1 mice.

In summary, our results suggest a crucial role for CB1 receptor in the progression of AD-related pathological events.”

 https://www.ncbi.nlm.nih.gov/pubmed/30096288
https://www.sciencedirect.com/science/article/abs/pii/S0006295218303277

Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials.

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“Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects.

Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system.

These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well.

Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD.

The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.”

https://www.ncbi.nlm.nih.gov/pubmed/30087591

https://www.frontiersin.org/articles/10.3389/fnins.2018.00502/full