Category Archives: Endocannabinoid System

Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents.

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“Cancer is the second leading cause of death in the United States with 1.7 million new cases estimated to be diagnosed in 2016. This disease remains a formidable clinical challenge and represents a substantial financial burden to the US health care system. Therefore, research and development of novel therapeutics for the treatment of cancer is of high priority.

Cannabinoids and their derivatives have been utilized for their medicinal and therapeutic properties throughout history.

Cannabinoid activity is regulated by the endocannabinoid system (ECS), which is comprised of cannabinoid receptors, transporters, and enzymes involved in cannabinoid synthesis and breakdown.

More recently, cannabinoids have gained special attention for their role in cancer cell proliferation and death. However, many studies investigated these effects using in vitro models which may not adequately mimic tumor growth and metastasis.

As such, this article aims to review study results which evaluated effects of cannabinoids from plant, synthetic and endogenous origins on cancer development in preclinical animal models and to examine the current standing of cannabinoids that are being tested in human cancer patients.” https://www.ncbi.nlm.nih.gov/pubmed/27774065

“The studies reviewed herein indicate that cannabinoids elicit activity through cannabinoid receptor dependent and independent pathways. The evidence generated in these human studies are still informative and, when taken together with the strong in vivo animal data demonstrating anti-tumor effects of cannabinoids, offer promise for a clinical role for cannabinoids in the eradication of tumors. Hence, these investigations shed light on the role of cannabinoids on tumor growth in vivo and may ultimately pave the way for the development of novel cannabinoid therapeutics for cancer treatment.”  http://journal.frontiersin.org/article/10.3389/fphar.2016.00361/full

Cannabinoid Receptor 2 Activation Restricts Fibrosis and Alleviates Hydrocephalus after Intraventricular Hemorrhage.

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“Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH).

The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases.

However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model.

In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-β1.”

https://www.ncbi.nlm.nih.gov/pubmed/27769788

Targeting cannabinoid receptor-2 pathway by phenylacetylamide suppresses the proliferation of human myeloma cells through mitotic dysregulation and cytoskeleton disruption.

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“Cannabinoid receptor-2 (CB2) is expressed dominantly in the immune system, especially on plasma cells.

Cannabinergic ligands with CB2 selectivity emerge as a class of promising agents to treat CB2-expressing malignancies without psychotropic concerns.

In this study, we found that CB2 but not CB1 was highly expressed in human multiple myeloma (MM) and primary CD138+ cells.

Thus, targeting CB2 may represent an attractive approach to treat cancers of immune origin.”

https://www.ncbi.nlm.nih.gov/pubmed/25640641

Crystal Structure of the Human Cannabinoid Receptor CB1.

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“Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use.

CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders.

Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study.

The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding.

In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids.

This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.”

https://www.ncbi.nlm.nih.gov/pubmed/27768894

Therapeutic potential of fatty acid amide hydrolase, monoacylglycerol lipase, and N-acylethanolamine acid amidase inhibitors.

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“Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anti-cancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2), or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation.

FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase-2 (COX-2).

Over the last decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their anti-nociceptive and anti-inflammatory effects, as well as protecting the nervous system.”

 https://www.ncbi.nlm.nih.gov/pubmed/27766867

Overexpression of cannabinoid receptor 1 promotes renal cell carcinoma progression.

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“Renal cell carcinoma (RCC) is a common urologic tumor with a poor prognosis.

Cannabinoid receptor 1 (CB1), which is a G protein-coupled receptor, has recently been reported to participate in the genesis and development of various cancers.

However, the exact role of CB1 in RCC is unknown. The aim of this study was to determine the role of CB1 in RCC cell lines and RCC prognosis, thus underlying its potential as a therapeutic target.

CB1 expression is functionally associated to cellular proliferation, apoptosis, and invasion ability of RCC.

Our data suggest that CB1 might be a potential target for RCC clinical therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/27757850

ENDOCANNABINOIDS AND SLEEP.

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“Sleep is regulated by several brain structures, neurotransmitters and neuromodulators.

Endocannabinoids (eCBs) are a group of lipids with modulatory activity in the brain and bind mainly to cannabinoid receptors CB1R and CB2R, thereby modulating several brain functions, (memory, mood, food intake, pain perception).

Oleoylethanolamide and palmitoylethanolamide belong to the N-acylethanolamides (NAEs) family, another type of active endogenous lipids. They bind to the peroxisome proliferator-activated receptor α but not to CB1R, thereby modulating food satiety, inflammation and pain.

Both eCBs and NAEs seem to be regulating the sleep-wake cycle.

Our objective is to analyze the experimental evidence published in the literature and to discuss if eCBs and NAEs are actually sleep modulators.

Studies suggested 1. eCBs and NAEs are under circadian control. 2. NAEs promote wake. 3. eCBs promote non-rapid-eye movement. 4. eCBs also promote rapid-eye-movement sleep by interacting with melanin-concentrating hormone neurons in the lateral hypothalamus. 5. The pharmacological blockade of the CB1R reduces sleep while increasing wake. 6. eCBs restore sleep in a model of insomnia in rats.”

https://www.ncbi.nlm.nih.gov/pubmed/27756691

Mild Traumatic Brain Injury Produces Neuron Loss That Can Be Rescued by Modulating Microglial Activation Using a CB2 Receptor Inverse Agonist.

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“We have previously reported that mild TBI created by focal left-side cranial blast in mice produces widespread axonal injury, microglial activation, and a variety of functional deficits.

We have also shown that these functional deficits are reduced by targeting microglia through their cannabinoid type-2 (CB2) receptors using 2-week daily administration of the CB2 inverse agonist SMM-189.

Overall, our findings indicate that SMM-189 rescues damaged neurons and thereby alleviates functional deficits resulting from TBI, apparently by selectively modulating microglia to the beneficial M2 state.

CB2 inverse agonists thus represent a promising therapeutic approach for mitigating neuroinflammation and neurodegeneration.”

 https://www.ncbi.nlm.nih.gov/pubmed/27766068

Structure of primary cannabinoid receptor is revealed

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“Findings give insight into designing safe and effective cannabinoid medications.”

Illustration of the CB1 receptor.

“New research is providing a more detailed view into the structure of the human cannabinoid (CB1) receptor. These findings provide key insights into how natural and synthetic cannabinoids including tetrahydrocannabinol (THC)—a primary chemical in marijuana—bind at the CB1 receptor to produce their effects. The research was funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.”

https://www.nih.gov/news-events/news-releases/structure-primary-cannabinoid-receptor-revealed

“‘Marijuana receptor’ uncovered in new study”  http://www.medicalnewstoday.com/articles/313564.php

N-Oleoylethanolamine Reduces Inflammatory Cytokines and Adhesion Molecules in TNF-α-induced Human Umbilical Vein Endothelial Cells by Activating CB2 and PPAR-α.

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“Inflammation plays a pivotal role in the pathogenesis of atherosclerosis.

Peroxisome proliferator-activated receptor-alpha (PPAR-α) and cannabinoid receptor 2 (CB2) crucially impact the modulation of inflammation.

N-Oleoylethanolamine (OEA), a natural agonist of PPAR-α, can also up-regulate the expression of CB2 in human umbilical vein endothelial cells (HUVECs) and further shows an antiatherosclerotic effect.

Our study was designed to determinate whether OEA could inhibit inflammation in HUVECs induced by tumor necrosis factor-α (TNF-α) and to identify the mechanism of OEA function.

These results suggest that OEA exerts anti-inflammatory and anti-adhesive effects on HUVECs.”

https://www.ncbi.nlm.nih.gov/pubmed/27281236