Category Archives: Endocannabinoid System

AM-1241 CB2 Receptor Agonist Attenuates Inflammation, Apoptosis and Stimulate Progenitor Cells in Bile Duct Ligated Rats.

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 “The cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator of liver disease.

Cannabinoid CB2 receptor activation has been reported to attenuate liver fibrosis in CCl4 exposed mice and also plays a potential role in liver regeneration in a mouse model of I/R and protection against alcohol-induced liver injury.

AIM:

In this study, we investigated the impact of CB2 receptors on the antifibrotic and regenerative process associated with cholestatic liver injury.

RESULTS:

Following bile duct ligation (BDL) for 3 weeks, there was increased aminotransferase levels, marked inflammatory infiltration and hepatocyte apoptosis with induced oxidative stress, as reflected by increased lipid peroxidation. Conversely, following treatment with the CB2 agonist, AM-1241, BDL rats displayed a reduction in liver injury and attenuation of fibrosis as reflected by expression of hydroxyproline and α-smooth muscle actin. AM1241 treatment also significantly attenuated lipid peroxidation end-products, p53-dependent apoptosis and also attenuated inflammatory process by stimulating IL-10 production. Moreover, AM1241 treated rats were associated with significant expression of hepatic progenitor/oval cell markers.

CONCLUSION:

In conclusion, this study points out that CB2 receptors reduce liver injury and promote liver regeneration via distinct mechanisms including IL-10 dependent inhibition of inflammation, reduction of p53-reliant apoptosis and through stimulation of oval/progenitor cells. These results suggest that CB2 agonists display potent hepatoregenrative properties, in addition to their antifibrogenic effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30976335

https://www.id-press.eu/mjms/article/view/oamjms.2019.194

Ketamine-induced antidepressant like effects in mice: A possible involvement of cannabinoid system.

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Biomedicine & Pharmacotherapy

“The purpose of this study was to explore the possible interaction between ketamine and cannabinoid system in the modulation of depression-related responses.

It seems that possible interaction between ketamine and cannabinoid system may modulate depression-related behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/30970516

https://www.sciencedirect.com/science/article/pii/S0753332218375309?via%3Dihub

“Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/
http://www.thctotalhealthcare.com/category/depression-2/

Circulating endocannabinoid concentrations and sexual arousal in women.

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The Journal of Sexual Medicine - Click here to go back to the homepage

“Several lines of evidence point to the potential role of the endocannabinoid system in female sexual functioning. These include results from studies describing the subjective effects of exogenous cannabinoids on sexual functioning in humans and the observable effects of exogenous cannabinoids on sexual functioning in other species, as well as results from studies investigating the location of cannabinoid receptors in the brain and periphery, and the effects of cannabinoid receptor activation on neurotransmitters implicated in sexual functioning. While these lines of research suggest a role for the endocannabinoid system in female sexual functioning, no studies investigating the relationship between concentrations of endogenous cannabinoids (i.e., arachidonoylethanolamide [AEA] and 2-arachidonoylglycerol [2-AG]) and sexual functioning have been conducted in any species.

AIM:

To measure circulating endocannabinoid concentrations in relation to subjective and physiological indices of sexual arousal in women (N = 21).

METHODS:

Serum endocannabinoid (AEA and 2-AG) concentrations were measured immediately prior to, and immediately following, viewing of neutral (control) and erotic (experimental) film stimuli in a repeated measures design. Physiological sexual arousal was measured via vaginal photoplethysmography. Subjective sexual arousal was measured both continuously and noncontinuously. Pearson’s correlations were used to investigate the relationships between endocannabinoid concentrations and sexual arousal.

MAIN OUTCOME MEASURES:

Changes in AEA and 2-AG concentrations from pre- to post-film and in relation to physiological and subjective indices of sexual arousal.

RESULTS:

Results revealed a significant relationship between endocannabinoid concentrations and female sexual arousal, whereby increases in both physiological and subjective indices of sexual arousal were significantly associated with decreases in AEA, and increases in subjective indices of sexual arousal were significantly associated with decreases in 2-AG.

CONCLUSIONS:

These findings support the hypothesis that the endocannabinoid system is involved in female sexual functioning, with implications for furthering understanding of the biological mechanisms underlying female sexual functioning.”

https://www.ncbi.nlm.nih.gov/pubmed/22462722

https://www.jsm.jsexmed.org/article/S1743-6095(15)33996-5/fulltext

[Significance of the endocannabinoid system in migraine].

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“Based on the traditional pain-relieving effect of Cannabis species an endogenous cannabinoid like system was discovered in the human body. Endocannabinoids have important role in the homeostasis of the body, such as stress response and mood control, feeding behaviour, energy balance and metabolism, immunological processes, and also play important role in controlling pain processing. Previous studies suggested that an endocannabinoid dysfunction, namely endocannabinoid deficit, might contribute to the development of migraine and its chronification. Although, the exact nature of the relationship between migraine and endocannabinoid system is not fully understood yet, in this brief review we summarise research results suggesting that the endocannabinoid system may be a potential drug target in the migraine therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30962405

Cannabinoid interventions for PTSD: Where to next?

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Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Cannabinoids are a promising method for pharmacological treatment of post-traumatic stress disorder (PTSD). Despite considerable research devoted to the effect of cannabinoid modulation on PTSD symptomology, there is not a currently agreed way by which the cannabinoid system should be targeted in humans. In this review, we present an overview of recent research identifying neurological pathways by which different cannabinoid-based treatments may exert their effects on PTSD symptomology. We evaluate the strengths and weaknesses of each of these different approaches, including recent challenges presented to favourable options such as fatty acid amide hydrolase (FAAH) inhibitors. This article makes the strengths and challenges of different potential cannabinoid treatments accessible to psychological researchers interested in cannabinoid therapeutics and aims to aid selection of appropriate tools for future clinical trials.”

https://www.ncbi.nlm.nih.gov/pubmed/30946942

https://www.sciencedirect.com/science/article/pii/S027858461930034X?via%3Dihub

Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons.

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Neuropharmacology

“Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington’s disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoidsystem in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGLfloxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/30914306

https://www.sciencedirect.com/science/article/pii/S0028390819301066?via%3Dihub

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

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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Publication Cover

“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