Cannabinoids, the Heart of the Matter

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“Cardiovascular disease (CVD) is a global epidemic representing the leading cause of death in some Western countries. Endocannabinoids and cannabinoid‐related compounds may be a promising approach as therapeutic agents for cardiovascular diseases. This review highlights the potential of cannabinoids and their receptors as targets for intervention.

In summary, the endocannabinoid system is highly active in cardiovascular disease states. Modulation of the ECS, CB1, and TRPV1 antagonism, as well as CB2 agonism, have proven to modulate disease state and severity in CVD. Studies are underway to develop drugs to change the course of cardiovascular diseases.

If therapeutic potential resides in a single molecule component or a derivative, then production and regulation of the therapy are straightforward. If the efficacious agent is a complex mixture that reflects some or all of the secondary metabolome complexity of Cannabis sativa, then safe and consistent production become challenging.”  http://jaha.ahajournals.org/content/7/14/e009099https://www.ncbi.nlm.nih.gov/pubmed/30006489

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Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation.

 Neuropharmacology

“Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects.

Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects.

Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy.

Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/29981335

https://www.sciencedirect.com/science/article/pii/S0028390818303575?via%3Dihub

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Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer’s Disease.

“The pathogenesis of Alzheimer’s disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent.

The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition.

It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in microglia and in immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated migroglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD.

The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.”

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Role of the cannabinoid signaling in the brain orexin- and ghrelin-induced visceral antinociception in conscious rats.

Journal of Pharmacological Sciences

“We hypothesized that the cannabinoid (CB) system may mediate the brain orexin- or ghrelin-induced visceral antinociception. Intraperitoneal injection of either CB1/2 agonist, WIN 55212 or O-Arachidonoyl ethanolamine increased the threshold volume of colonic distension-induced abdominal withdrawal reflex in rats, suggesting CB could induce visceral antinociception. Pretreatment with either the CB1 or CB2 antagonist potently blocked the centrally injected orexin-A-induced antinociceptive action against colonic distension while CB2 but not CB1 antagonist blocked the brain ghrelin-induced visceral antinociception. These results suggest that the cannabinoid signaling may be involved in the central orexin- or ghrelin-induced antinociceptive action in a different mechanistic manner.”

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Cannabidiol did not induce teratogenicity or neurotoxicity in exposed zebrafish embryos.

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“Cannabidiol (CBD) is a non-psychotomimetic compound of the Cannabis sativa that has been used for the treatment of severe epilepsy as well as other diseases of nervous system. However, toxicity studies of CBD have great relevance to guarantee the patients safety.

In this context, morphological analyses of zebrafish can contribute to evaluate the teratogenic potential, as well as evaluation of acetylcholinesterase activity and motor activity of zebrafish are valuable tools to verify the neurotoxicity potential. In the present work, we use this methodology to test the toxicity of CBD to zebrafish embryos.

No malformation was observed in morphological analysis of embryos exposed to all tested concentrations of CBD.

Embryos exposed to CBD did not show differences in acetylcholinesterase activity, but embryos exposed to CBD 20-300 μg/L were 1.4 up to 1.7-fold more active when compared to the control. Despite that, at 48 hpf, motor activity returned to control values.

Our results suggest that the effects observed after CBD exposure are intimately related to CB1 receptor that is present in zebrafish since early stages of development. The present work showed early light effects induced by CBD exposure in concentrations that did not alter biochemical activity.”

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Cannabinoid receptor type 1 in the brain regulates the affective component of visceral pain in mice.

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“Endocannabinoids acting through cannabinoid receptor type 1 (CB1) are major modulators of peripheral somatic and visceral nociception. Although only partially studied, some evidence suggests a particular role of CB1 within the brain in nociceptive processes.

As the endocannabinoid system regulates affect and emotional behaviors, we hypothesized that cerebral CB1 influences affective processing of visceral pain-related behaviors in laboratory animals.

To study nocifensive responses modulated by supraspinal CB1, we used conditional knock-out mice lacking CB1 either in cortical glutamatergic neurons (Glu-CB1-KO), or in forebrain GABAergic neurons (GABA-CB1-KO), or in principle neurons of the forebrain (CaMK-CB1-KO). These mutant mice and mice treated with the CB1 antagonist SR141716 were tested for different pain-related behaviors. In an acetic acid-induced abdominal constriction test, supraspinal CB1 deletions did not affect nocifensive responses. In the cerulein-model of acute pancreatitis, mechanical allodynia or hyperalgesia were not changed, but Glu-CB1- and CaMK-CB1-KO mice showed significantly increased facial grimacing scores indicating increased affective responses to this noxious visceral stimulus. Similarly, these brain-specific CB1 KO mice also showed significantly changed thermal nociception in a hot-plate test.

These results reveal a novel, and important role of CB1 expressed by cortical glutamatergic neurons in the affective component of visceral nociception.”

https://www.ncbi.nlm.nih.gov/pubmed/29885522

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Assessment of Cannabinoids Agonist and Antagonist in Invasion Potential of K562 Cancer Cells

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“The prominent hallmark of malignancies is the metastatic spread of cancer cells. Recent studies have reported that the nature of invasive cells could be changed after this phenomenon, causing chemotherapy resistance.

It has been demonstrated that the up-regulated expression of matrix metalloproteinase (MMP) 2/MMP-9, as a metastasis biomarker, can fortify the metastatic potential of leukemia.

Furthermore, investigations have confirmed the inhibitory effect of cannabinoid and endocannabinoid on the proliferation of cancer cells in vitro and in vivo.

Our findings clarifies that CB1 receptors are responsible for anti-invasive effects in the K562 cell line.”

https://www.ncbi.nlm.nih.gov/pubmed/29883990

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Endocannabinoid and Muscarinic Signaling Crosstalk in the 3xTg-AD Mouse Model of Alzheimer’s Disease.

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“The endocannabinoid system, which modulates emotional learning and memory through CB1 receptors, has been found to be deregulated in Alzheimer’s disease (AD).

AD is characterized by a progressive decline in memory associated with selective impairment of cholinergic neurotransmission. The functional interplay of endocannabinoid and muscarinic signaling was analyzed in seven-month-old 3xTg-AD mice following the evaluation of learning and memory of an aversive stimulus.

The subchronic (seven days) stimulation of the endocannabinoid system following repeated WIN55,212-2 (1 mg/kg) or JZL184 (8 mg/kg) administration induced a CB1 receptor downregulation and CB1-mediated signaling desensitization, normalizing acquisition latencies to control levels. However, the observed modulation of cholinergic neurotransmission in limbic areas did not modify learning and memory outcomes.

A CB1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD.”

https://www.ncbi.nlm.nih.gov/pubmed/29865071

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180137

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Anti-Tumorigenic Properties of Omega-3 Endocannabinoid Epoxides.

Journal of Medicinal Chemistry

“Accumulating studies have linked inflammation to tumor progression.

Dietary omega-3 fatty acids including docosahexaenoic acid (DHA) have been shown to suppress tumor growth through their conversion to epoxide metabolites. Alternatively, DHA is converted enzymatically into docosahexaenoylethanolamide (DHEA), an endocannabinoid with anti-proliferative activity.

Recently, we reported a novel class of anti-inflammatory DHEA-epoxides (EDP-EAs) that contain both ethanolamide and epoxide moieties. Herein we evaluate the anti-tumorigenic properties of EDP-EAs in an osteosarcoma model.

First, we show ~80% increase in EDP-EAs in metastatic lungs versus normal mouse lungs. We found significant differences in the apoptotic and anti-migratory potency of the different EDP-EA regioisomers, which are partly mediated through cannabinoid receptor 1 (CB1).

Furthermore, we synthesized derivatives of the most pro-apoptotic regioisomer. These derivatives had reduced hydrolytic susceptibility to fatty acid-amide hydrolase and increased CB1 binding.

Collectively, we report a novel class of EDP-EAs that exhibit anti-angiogenic, anti-tumorigenic and anti-migratory properties in osteosarcoma.”

https://www.ncbi.nlm.nih.gov/pubmed/29856219

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00243

“Omega-3 Fatty Byproducts May Have Anticancer Effects.https://scienceblog.com/502227/omega-3-fatty-byproducts-may-have-anticancer-effects/
“Products of omega-3 fatty acid metabolism may have anticancer effects, study shows” https://medicalxpress.com/news/2018-07-products-omega-fatty-acid-metabolism.html
“Omega-3-derived cannabinoid may stop cancer. New research suggests that the body’s natural pain-killer, the “endocannabinoid system,” may also have cancer-fighting properties when “activated” by omega-3 fatty acids.” https://www.medicalnewstoday.com/articles/322482.php
“Products of omega-3 fatty acid metabolism may have anticancer effects” https://www.sciencedaily.com/releases/2018/07/180713220137.htm
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Methods to Quantify Cell Signaling and GPCR Receptor Ligand Bias: Characterization of Drugs that Target the Endocannabinoid Receptors in Huntington’s Disease.

Huntington’s Disease

“G protein-coupled receptors (GPCRs) interact with multiple intracellular effector proteins such that different ligands may preferentially activate one signal pathway over others, a phenomenon known as signaling bias. Signaling bias can be quantified to optimize drug selection for preclinical research.

Here, we describe moderate-throughput methods to quantify signaling bias of known and novel compounds. In the example provided, we describe a method to define cannabinoid-signaling bias in a cell culture model of Huntington’s disease (HD).

Decreasing type 1 cannabinoid receptor (CB1) levels is correlated with chorea and cognitive deficits in HD. There is evidence that elevating CB1 levels and/or signaling may be beneficial for HD patients while decreasing CB1 levels and/or signaling may be detrimental.

Recent studies have found that Gαi/o-biased CB1 agonists activate extracellular signal-regulated kinase (ERK), increase CB1 protein levels, and improve viability of cells expressing mutant huntingtin. In contrast, CB1 agonists that are β-arrestin1-biased were found to reduce CB1 protein levels and cell viability.

Measuring agonist bias of known and novel CB1 agonists will provide important data that predict CB1-specific agonists that might be beneficial in animal models of HD and, following animal testing, in HD patients. This method can also be applied to study signaling bias for other GPCRs.”

https://www.ncbi.nlm.nih.gov/pubmed/29856035

https://link.springer.com/protocol/10.1007%2F978-1-4939-7825-0_25

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