Monthly Archives: March 2019

Protective effects of specific cannabinoid receptor 2 agonist GW405833 on concanavalin A-induced acute liver injury in mice.

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“Cannabinoid receptor 2 (CB2R) is highly expressed in immune cells and plays an important role in regulating immune responses. In the current study, we investigated the effects of GW405833 (GW), a specific CB2R agonist, on acute liver injury induced by concanavalin A (Con A).

In animal experiments, acute liver injury was induced in mice by injection of Con A (20 mg/kg, i.v.). The mice were treated with GW (20 mg/kg, i.p., 30 min after Con A injection) or GW plus the selective CB2R antagonist AM630 (2 mg/kg, i.p., 15 min after Con A injection).

We found that Con A caused severe acute liver injury evidenced by significantly increased serum aminotransferase levels, massive hepatocyte apoptosis, and necrosis, as well as lymphocyte infiltration in liver tissues. Treatment with GW significantly ameliorated Con A-induced pathological injury in liver tissue, decreased serum aminotransferase levels, and decreased hepatocyte apoptosis.

Our results suggest that GW protects against Con A-induced acute liver injury in mice by inhibiting Jurkat T-cell proliferation through the CB2Rs.”

https://www.ncbi.nlm.nih.gov/pubmed/30918343

https://www.nature.com/articles/s41401-019-0213-0

Update on Antiepileptic Drugs 2019.

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“This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use.

RECENT FINDINGS:

Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity.Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug’s efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action.

SUMMARY:

Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/30921021

https://insights.ovid.com/crossref?an=00132979-201904000-00014

Joints for joints: cannabinoids in the treatment of rheumatoid arthritis.

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“An increasing number of patients with rheumatoid arthritis (RA) are using cannabis to treat their symptoms, although systematic studies regarding efficacy in RA are lacking. Within this review we will give an overview on the overall effects of cannabinoids in inflammation and why they might be useful in the treatment of RA.

RECENT FINDINGS:

Peripherally, cannabinoids show anti-inflammatory effects by activating cannabinoid type 2 receptors (CB2) which decrease cytokine production and immune cell mobilization. In contrast, cannabinoid type 1 receptor (CB1) activation on immune cells is proinflammatory while CB1 antagonism provides anti-inflammatory effects by increasing β2-adrenergic signaling in the joint and secondary lymphoid organs. In addition, the nonpsychotropic cannabinoid, cannabidiol (CBD) demonstrated antiarthritic effects independent of cannabinoid receptors. In addition to controlling inflammation, cannabinoids reduce pain by activating central and peripheral CB1, peripheral CB2 receptors and CBD-sensitive noncannabinoid receptor targets.

SUMMARY:

Cannabinoids might be a suitable treatment for RA, but it is important to target the right receptors in the right place. For clinical studies, we propose a combination of a CB2 agonist to decrease cytokine production, a peripheral CB1 antagonist to prevent detrimental CB1 signaling and to support anti-inflammatory effects of CB2 via activation of β2-adrenergic receptors and CBD to induce cannabinoid-receptor-independent anti-inflammatory effects.”

 https://www.ncbi.nlm.nih.gov/pubmed/30920973
https://insights.ovid.com/crossref?an=00002281-201905000-00009

Investigating the Relationships Between Alcohol Consumption, Cannabis Use, and Circulating Cytokines: A Preliminary Analysis.

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Alcoholism: Clinical and Experimental Research banner

“In recent years, human and animal studies have converged to support altered inflammatory signaling as a molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD. Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation. Thus, the impact of cannabis on inflammation in AUDs in humans warrants examination.

METHODS:

We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-8, and IL-1β in the blood. Among 66 regular drinkers (mean age = 30.08), we examined circulating cytokines and administered questionnaires assessing alcohol consumption and days of cannabis use over the past 90 days. We examined whether alcohol consumption, cannabis use, and gender were associated with changes in circulating cytokines, and whether there was a significant interaction between alcohol and cannabis use predicting blood levels of circulating cytokines.

RESULTS:

A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1β. Follow-up moderation analyses indicated a cannabis by alcohol interaction predicting circulating IL-6, such that cannabis nonusers showed a stronger relationship between alcohol and IL-6 compared to cannabis users.

CONCLUSIONS:

These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use. In addition, the present results provide data to inform future investigations, with the goal of ultimately leveraging knowledge of the role of inflammation in AUDs to develop more effective treatments focused on novel immune targets.”

https://www.ncbi.nlm.nih.gov/pubmed/29286537

https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.13592

Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders.

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The Lancet Neurology

“In the past two decades, there has been an increasing interest in the therapeutic potential of cannabinoids for neurological disorders such as epilepsy, multiple sclerosis, pain, and neurodegenerative diseases. Cannabis-based treatments for pain and spasticity in patients with multiple sclerosis have been approved in some countries. Randomised controlled trials of plant-derived cannabidiol for treatment of Lennox-Gastaut syndrome and Dravet syndrome, two severe childhood-onset epilepsies, provide evidence of anti-seizure effects. Despite positive results in these two severe epilepsy syndromes, further studies are needed to determine if the anti-seizure effects of cannabidiol extend to other forms of epilepsy, to overcome pharmacokinetic challenges with oral cannabinoids, and to uncover the exact mechanisms by which cannabidiol or other exogenous and endogenous cannabinoids exert their therapeutic effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30910443

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(19)30032-8/fulltext

Cannabidiol: Recent advances and new insights for neuropsychiatric disorders treatment.

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Life Sciences

“The pharmacological research on the Cannabis sativa-derived compounds has never terminated. Among the phytocannabinoids without psychotropic effects, the prevalent one in Cannabis is cannabidiol (CBD). Although CBD was initially considered a type 2 cannabinoid receptor (CB2R) antagonist, it did not show a good cannabinoidergic activity. Furthermore, heterogeneous results were obtained in experimental animal models of anxiety disorders, psychotic stages and neurodegenerative diseases. Recently, CBD has been authorized by the FDA to treat some rare forms of epilepsy and many trials have begun for the treatment of autism spectrum disorders. This review aims to clarify the pharmacological activity of CBD and its multiple therapeutic applications. Furthermore, critical and conflicting results of the research on CBD are discussed with a focus on promising future prospects.”

https://www.ncbi.nlm.nih.gov/pubmed/30910646

https://www.sciencedirect.com/science/article/abs/pii/S0024320519302176?via%3Dihub

In-silico designing and characterization of binding modes of two novel inhibitors for CB1 receptor against obesity by classical 3D-QSAR approach.

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Journal of Molecular Graphics and Modelling

“Obesity is the fifth primary hazard for mortality in the world; hence different therapeutic targets are explored to overcome this problem.

Endocannabinoid is identified as the emerging target for the treatment of obesity as Cannabinoid 1 (CB1) receptor over-activation resulted in abdominal obesity.

Potent antagonists or inverse agonists for CB1 receptor are the new strategies to develop anti-obesity drugs.

The obtained results signify the potential of the developed model; suggesting that the models can be useful to test and design potent novel CB1 receptor antagonists or inverse agonists prior to the synthesis.”

https://www.ncbi.nlm.nih.gov/pubmed/30908997

“Potent antagonists or inverse agonists for CB1 receptor are the new strategies to develop anti-obesity drugs.”

https://www.sciencedirect.com/science/article/pii/S1093326318308398?via%3Dihub

A patent update on cannabinoid receptor 1 antagonists (2015-2018).

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“The endocannabinoid system is an important regulator of various physiological processes. Preclinical and clinical studies indicate that attenuation of the endocannabinoid system via antagonism of the type 1 cannabinoid receptor (CB1) is an excellent strategy to treat obesity, metabolic syndrome and associated disorders. However, centrally acting antagonists of CB1 also produce adverse effects like depression and anxiety. Current efforts are geared towards discovery and optimization of antagonists and modulators of CB1 that have limited brain penetration. Areas Covered: Several recent publications and patent applications support the development of peripherally acting CB1 receptor antagonists and modulators. In this review, recent patents and applications (2015 – 2018) are summarized and discussed. Expert Opinion: Approximately 30 new inventions have been reported since 2015, along with 3 recent commercial deals, highlighting the importance of this class of therapeutics. Taken together, peripherally acting CB1 receptor antagonists and modulators are an emerging class of drugs for metabolic syndrome, non-alcoholic steatohepatitis (NASH) and other important disorders where this receptor has been implicated.”

https://www.ncbi.nlm.nih.gov/pubmed/30889997

https://www.tandfonline.com/doi/abs/10.1080/13543776.2019.1597851?journalCode=ietp20

Cannabinoid CB2R receptors are upregulated with corneal injury and regulate the course of corneal wound healing.

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Experimental Eye Research

“CB2R receptors have demonstrated beneficial effects in wound healing in several models. We therefore investigated a potential role of CB2R receptors in corneal wound healing. We examined the functional contribution of CB2R receptors to the course of wound closure in an in vivo murine model. We additionally examined corneal expression of CB2R receptors in mouse and the consequences of their activation on cellular signaling, migration and proliferation in cultured bovine corneal epithelial cells (CECs). Using a novel mouse model, we provide evidence that corneal injury increases CB2R receptor expression in cornea. The CB2R agonist JWH133 induces chemorepulsion in cultured bovine CECs but does not alter CEC proliferation. The signaling profile of CB2R activation is activating MAPK and increasing cAMP accumulation, the latter perhaps due to Gs-coupling. Lipidomic analysis in bovine cornea shows a rise in acylethanolamines including the endocannabinoid anandamide 1 h after injury. In vivo, CB2R deletion and pharmacological block result in a delayed course of wound closure. In summary, we find evidence that CB2R receptor promoter activity is increased by corneal injury and that these receptors are required for the normal course of wound closure, possibly via chemorepulsion.”

https://www.ncbi.nlm.nih.gov/pubmed/30905716

https://www.sciencedirect.com/science/article/pii/S0014483518307206?via%3Dihub

Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration.

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 “The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids.

METHODS:

We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro.

RESULTS:

Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis.

CONCLUSIONS:

The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.”

https://www.ncbi.nlm.nih.gov/pubmed/30899454

https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-019-0148-x