Novel Anti-inflammatory and Vasodilatory ω-3 Endocannabinoid Epoxide Regioisomers.

 “Accumulating evidence suggests that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) offer protection against vascular inflammation, neuroinflammation, hypertension, and thrombosis.

Recently, biochemical studies have demonstrated that these benefits are partially mediated by their conversion to ω-3 endocannabinoid epoxide metabolites. These lipid metabolites originate from the epoxidation of ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by cytochrome P450 (CYP) epoxygenases to form epoxydocosapentaenoic acid-ethanolamides (EDP-EAs) and epoxyeicosatetraenoic acid-ethanolamides (EEQ-EAs), respectively.

The EDP-EAs and EEQ-EAs are endogenously produced in rat brain and peripheral organs. Additionally, EDP-EAs and EEQ-EAs dose-dependently decrease pro-inflammatory IL-6 cytokine and increased anti-inflammatory IL-10 cytokine. Furthermore, the EEQ-EAs and EDP-EAs attenuate angiogenesis and cell migration in cancer cells, induce vasodilation in bovine coronary arteries, and reciprocally regulate platelet aggregation in washed human platelets.

Taken together, the ω-3 endocannabinoid epoxides represent a new class of dual acting molecules that display unique pharmacological properties.”

https://www.ncbi.nlm.nih.gov/pubmed/31562632

https://link.springer.com/chapter/10.1007%2F978-3-030-21735-8_17

The non-euphoric phytocannabinoid cannabidivarin counteracts intestinal inflammation in mice and cytokine expression in biopsies from UC pediatric patients.

Pharmacological Research“Patients with ulcerative colitis (UC) using marijuana have been reported to experience symptomatic benefit.

Cannabidivarin (CBDV) is a safe non-psychoactive phytocannabinoid able to activate TRPA1, a member of TRP channels superfamily, which plays a pivotal role in intestinal inflammation.

Here, we have investigated the potential intestinal anti-inflammatory effect of CBDV in mice and in biopsies from pediatric patients with active UC.

Our preclinical study shows that CBDV exerts intestinal anti-inflammatory effects in mice via TRPA1, and in children with active UC.

Since CBDV has a favorable safety profile in humans, it may be considered for possible clinical trials in patients with UC.”

https://www.ncbi.nlm.nih.gov/pubmed/31553934

https://linkinghub.elsevier.com/retrieve/pii/S1043661819311077

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation.

 Image result for journal of geriatric psychiatry and neurology

“The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation.

We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38).

These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.”

https://www.ncbi.nlm.nih.gov/pubmed/31547752

https://journals.sagepub.com/doi/abs/10.1177/0891988719874118?journalCode=jgpb

Selective Cannabinoid 2 Receptor Agonists as Potential Therapeutic Drugs for the Treatment of Endotoxin-Induced Uveitis.

molecules-logo“The cannabinoid 2 receptor (CB2R) is a promising anti-inflammatory drug target and development of selective CB2R ligands may be useful for treating sight-threatening ocular inflammation. This study examined the pharmacology of three novel chemically-diverse selective CB2R ligands. These unique ligands are potent and selective for CB2R and have good immunomodulating actions in the eye. The data generated with these three structurally-diverse and highly-selective CB2R agonists support selective targeting of CB2R for treating ocular inflammatory diseases.”
https://www.ncbi.nlm.nih.gov/pubmed/31540271
https://www.mdpi.com/1420-3049/24/18/3338

Druggable Targets of the Endocannabinoid System: Implications for the Treatment of HIV-Associated Neurocognitive Disorder.

Brain Research“HIV-associated neurocognitive disorder (HAND) affects nearly half of all HIV-infected individuals. Synaptodendritic damage correlates with neurocognitive decline in HAND, and many studies have demonstrated that HIV-induced neuronal injury results from excitotoxic and inflammatory mechanisms.

The endocannabinoid (eCB) system provides on-demand protection against excitotoxicity and neuroinflammation.

Here, we discuss evidence of the neuroprotective and anti-inflammatory properties of the eCB system from in vitro and in vivo studies. We examine the pharmacology of the eCB system and evaluate the therapeutic potential of drugs that modulate eCB signaling to treat HAND.

Finally, we provide perspective on the need for additional studies to clarify the role of the eCB system in HIV neurotoxicity and speculate that strategies that enhance eCB signaling might slow cognitive decline in HAND.”

https://www.ncbi.nlm.nih.gov/pubmed/31539547

https://www.sciencedirect.com/science/article/abs/pii/S0006899319305219?via%3Dihub

The Impact of Cannabinoid Receptor 2 Deficiency on Neutrophil Recruitment and Inflammation.

View details for DNA and Cell Biology cover image“Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines.

A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB2) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury.

Recent work in preclinical models of inflammation raises two questions: by what mechanisms do CB2 agonists provide anti-inflammatory effects during acute inflammation and what challenges exist in the translation of CB2 modulating therapeutics into the clinic.”

Insights into the role of cannabis in the management of inflammatory bowel disease.

Image result for therapeutic advances in gastroenterology“Cannabis, a drug made up of the flowers and buds of the Cannabis sativa plant, has been used therapeutically for centuries. Ancient Chinese cultures have reported use in their medical practices, dating back as early as 2700 BC.  Although widely used recreationally during the 19th and 20th centuries, the use of medical cannabis has exploded over the last decade, as a result of mainstream cultural acceptance and legalization in several countries around the world.

Over the last decade, interest in the therapeutic potential of cannabis and its constituents (e.g. cannabidiol) in the management of inflammatory bowel diseases (IBD) has escalated. Cannabis has been increasingly approved for a variety of medical conditions in several jurisdictions around the world.

In animal models, cannabinoids have been shown to improve intestinal inflammation in experimental models of IBD through their interaction with the endocannabinoid system. However, the few randomized controlled trials of cannabis or cannabidiol in patients with IBD have not demonstrated efficacy in modulating inflammatory disease activity.

Cannabis may be effective in the symptomatic management of IBD. Given the increasing utilization and cultural acceptance of cannabis, physicians need to be aware of its safety and efficacy in order to better counsel patients. The aim of this review is to provide an overview of the role of cannabis in the management of patients with IBD.

There is emerging evidence that cannabis may play a role in the management of patients with IBD. Many patients are already using cannabis to help manage symptoms associated with the disease, and physicians cannot ignore this when taking histories and managing their patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31523278

https://journals.sagepub.com/doi/10.1177/1756284819870977

Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression.

Brain, Behavior, and Immunity“Depression is a well-recognised effect of long-term treatment with interferon-alpha (IFN-α), a widely used treatment for chronic viral hepatitis and malignancy. In addition to the emotional disturbances, high incidences of painful symptoms such as headache and joint pain have also been reported following IFN-α treatment.

The endocannabinoid system plays an important role in emotional and nociceptive processing, however it is unknown whether repeated IFN-α administration induces alterations in this system.

The present study investigated nociceptive responding in the IFN-α-induced mouse model of depression and associated changes in the endocannabinoid system. Furthermore, the effects of modulating peripheral endocannabinoid tone on inflammatory pain-related behaviour in the IFN-α model was examined.

In summary, increasing peripheral endocannabinoid tone attenuates inflammatory hyperalgesia induced following repeated IFN-α administration. These data provide support for the endocannabinoid system in mediating and modulating heightened pain responding associated with IFNα-induced depression.”

https://www.ncbi.nlm.nih.gov/pubmed/31505257

“Inflammatory hyperalgesia is associated with altered endocannabinoid levels. Enhancing peripheral endocannabinoid tone attenuates IFN-α related hyperalgesia.”

https://www.sciencedirect.com/science/article/pii/S0889159119306063?via%3Dihub

Combination of Cannabinoids, Δ9- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways.

 Image result for frontiers in immunology“Multiple sclerosis (MS) is a chronic and disabling disorder of the central nervous system (CNS) characterized by neuroinflammation leading to demyelination.

Recently a combination of Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) extracted from Cannabis has been approved in many parts of the world to treat MS-related spasticity. THC+CBD combination was also shown to suppresses neuroinflammation, although the mechanisms remain to be further elucidated.

In the current study, we demonstrate that THC+CBD combination therapy (10 mg/kg each) but not THC or CBD alone, attenuates murine experimental autoimmune encephalomyelitis (EAE) by reducing neuroinflammation and suppression of Th17 and Th1 cells.

Collectively, this study suggests that combination of THC+CBD suppresses neuroinflammation and attenuates clinical EAE development and that this effect is associated with changes in miRNA profile in brain-infiltrating cells.”

https://www.ncbi.nlm.nih.gov/pubmed/31497013

“Combination of THC+CBD has been used to treat human MS. This treatment is known to decrease not only muscle spasticity but also suppress neuroinflammation.”

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01921/full

The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept.

Publication cover image“Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss.

The aim of our study was to explore the potential role of the cannabinoid receptor 1 (CB1) during CAD.

Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology.”

https://www.ncbi.nlm.nih.gov/pubmed/31469511

https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.14570