Cannabinoid receptor-1 antagonism: a new perspective on treating a murine schistosomal liver fibrosis model.

 SciELO - Scientific Electronic Library Online“Formation of schistosomal granulomata surrounding the ova can result in schistosomiasis-associated liver fibrosis (SSLF). The current standard of treatment is praziquantel (PZQ), which cannot effectively reverse SSLF.

The role of the cannabinoid (CB) receptor family in liver fibrosis has recently been highlighted.

This study aimed to assess the therapeutic effect of CB1 receptor antagonism in reversing SSLF in a murine model of Schistosoma mansoni infection.

MAIN CONCLUSIONS:

Combining PZQ with CB1 receptor antagonists yielded the best results in reversing SSLF. To our knowledge, this is the first study to test this regimen in S. mansoni infection.”

https://www.ncbi.nlm.nih.gov/pubmed/31389521

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762019000100338&tlng=en

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Potential Mechanisms Influencing the Inverse Relationship Between Cannabis and Nonalcoholic Fatty Liver Disease: A Commentary.

Image result for Nutrition and Metabolic Insights“Nonalcoholic fatty liver disease (NAFLD) develops when the liver is unable to oxidize or export excess free fatty acids generated by adipose tissue lipolysis, de novo lipogenesis, or dietary intake. Although treatment has generally been centered on reversing metabolic risk factors that increase the likelihood of NAFLD by influencing lifestyle modifications, therapeutic modalities are being studied at the cellular and molecular level.

The endocannabinoid system has been of recent focus. The agonism and antagonism of cannabinoid receptors play roles in biochemical mechanisms involved in the development or regression of NAFLD. Exocannabinoids and endocannabinoids, the ligands which bind cannabinoid receptors, have been studied in this regard.

Exocannabinoids found in cannabis (marijuana) may have a therapeutic benefit. Our recent study demonstrated an inverse association between marijuana use and NAFLD among adults in the United States.

This commentary combines knowledge on the role of the endocannabinoid system in the setting of NAFLD with the findings in our article to hypothesize different potential mechanisms that may influence the inverse relationship between cannabis and NAFLD.” https://www.ncbi.nlm.nih.gov/pubmed/31308686

https://journals.sagepub.com/doi/10.1177/1178638819847480

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Cannabis consumption and non-alcoholic fatty liver disease. A three years longitudinal study in first episode non-affective psychosis patients.

Progress in Neuro-Psychopharmacology and Biological Psychiatry“Increased incidence of obesity and excess weight lead to an increased incidence of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates a protective effect of cannabis consumption on weight gain and related metabolic alterations in psychosis patients. Overall, patients are at greater risk of presenting fatty diseases, such as NAFLD, partly due to lipid and glycemic metabolic disturbances. However, there are no previous studies on the likely effect of cannabis on liver steatosis. We aimed to explore if cannabis consumption had an effect on hepatic steatosis, in a sample of first-episode (FEP) non-affective psychosis.

RESULTS:

At 3-year follow-up, cannabis users presented significantly lower FLI scores than non-users (F = 13.874; p < .001). Moreover, cannabis users less frequently met the criteria for liver steatosis than non-users (X2 = 7.97, p = .019). Longitudinally, patients maintaining cannabis consumption after 3 years presented the smallest increment in FLI over time, which was significantly smaller than the increment in FLI presented by discontinuers (p = .022) and never-users (p = .016). No differences were seen in fibrosis scores associated with cannabis.

CONCLUSIONS:

Cannabis consumption may produce a protective effect against liver steatosis in psychosis, probably through the modulation of antipsychotic-induced weight gain.”

https://www.ncbi.nlm.nih.gov/pubmed/31228640

“Cannabis consumption is associated with a lower risk of liver steatosis in psychosis. Cannabis use is not associated with liver fibrosis.”

https://www.sciencedirect.com/science/article/pii/S0278584619301393?via%3Dihub

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Endocannabinoid System in Hepatic Glucose Metabolism, Fatty Liver Disease, and Cirrhosis.

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“There is growing evidence that glucose metabolism in the liver is in part under the control of the endocannabinoid system (ECS) which is also supported by its presence in this organ. The ECS consists of its cannabinoid receptors (CBRs) and enzymes that are responsible for endocannabinoid production and metabolism. ECS is known to be differentially influenced by the hepatic glucose metabolism and insulin resistance, e.g., cannabinoid receptor type 1(CB1) antagonist can improve the glucose tolerance and insulin resistance. Interestingly, our own study shows that expression patterns of CBRs are influenced by the light/dark cycle, which is of significant physiological and clinical interest. The ECS system is highly upregulated during chronic liver disease and a growing number of studies suggest a mechanistic and therapeutic impact of ECS on the development of liver fibrosis, especially putting its receptors into focus. An opposing effect of the CBRs was exerted via the CB1 or CB2 receptor stimulation. An activation of CB1promoted fibrogenesis, while CB2 activation improved antifibrogenic responses. However, underlying mechanisms are not yet clear. In the context of liver diseases, the ECS is considered as a possible mediator, which seems to be involved in the synthesis of fibrotic tissue, increase of intrahepatic vascular resistance and subsequently development of portal hypertension. Portal hypertension is the main event that leads to complications of the disease. The main complication is the development of variceal bleeding and ascites, which have prognostic relevance for the patients. The present review summarizes the current understanding and impact of the ECS on glucose metabolism in the liver, in association with the development of liver cirrhosis and hemodynamics in cirrhosis and its complication, to give perspectives for development of new therapeutic strategies.”

https://www.ncbi.nlm.nih.gov/pubmed/31121839

https://www.mdpi.com/1422-0067/20/10/2516

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Effects of cannabidiol on alcohol-related outcomes: A review of preclinical and human research.

Cover image for Experimental and Clinical Psychopharmacology

“This article reviews preclinical and human studies examining the effects of CBD administration on alcohol responses. Preliminary preclinical results suggest that CBD can attenuate alcohol consumption and potentially protect against certain harmful effects of alcohol, such as liver and brain damage.”

https://www.ncbi.nlm.nih.gov/pubmed/31120285

https://psycnet.apa.org/doiLanding?doi=10.1037%2Fpha0000272

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Therapeutic prospects of cannabidiol for alcohol use disorder and alcohol-related damages on the liver and the brain

 Image result for frontiers in pharmacology“Cannabidiol (CBD) is a natural compound of cannabis, which exerts complex and widespread immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Many experimental data suggest that CBD could have several types of application in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver.

Experimental studies converge to find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, and by decreasing anxiety and impulsivity. Moreover, CBD has been shown to reduce alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and inducing death of activated hepatic stellate cells. Last, CBD has been found to reduce alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties.

CBD could directly reduce alcohol drinking in subjects with AUD. But other original applications warrant human trials in this population. By reducing alcohol-related processes of steatosis in the liver, and brain alcohol-related damage, CBD could improve both the hepatic and neurocognitive outcomes of subjects with AUD, regardless of the individual drinking trajectories. This might pave the way for testing new harm reduction approaches in AUD, i.e., for protecting the organs of subjects with an ongoing AUD.”

https://www.frontiersin.org/articles/10.3389/fphar.2019.00627/abstract

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Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome.

toxins-logo “In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB1R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB1R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB1R once again.”

https://www.ncbi.nlm.nih.gov/pubmed/31096702

https://www.mdpi.com/2072-6651/11/5/275

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Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-κB and NLRP3 inflammasome pathway.

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“Cannabidiol (CBD), an abundant nonpsychoactive constituent of marijuana, has been reported previously to protect against hepatic steatosis.

In this study, we studied further the functions and mechanisms of CBD on liver inflammation induced by HFC diet.

Mice feeding an HFC diet for 8 weeks were applied to test the protective effect of CBD on livers. RAW264.7 cells were incubated with LPS + ATP ± CBD to study the mechanisms of the effect of CBD against inflammasome activation.

We found that CBD alleviated liver inflammation induced by HFC diet.

CBD significantly inhibited the nuclear factor-κappa B (NF-κB) p65 nuclear translocation and the activation of nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome both in vivo and in vitro studies, which lead to the reduction of the expression of inflammation-related factors in our studies.

In addition, Inhibitor of activation of NF-κB partly suppressed the NLRP3 inflammasome activation, while adding CBD further inhibited NF-κB activation and correspondingly suppressed the NLRP3 inflammasome activation in macrophages.

In conclusion, the suppression of the activation of NLRP3 inflammasome through deactivation of NF-κB in macrophages by CBD might be one mechanism of its anti-inflammatory function in the liver.”

https://www.ncbi.nlm.nih.gov/pubmed/31032942

https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.28728

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

 “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

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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

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