Tag Archives: treatment

Cannabinoid receptors as new targets of antifibrosing strategies during chronic liver diseases.

Posted on by

Abstract

“Chronic liver injury exposes the patient to liver fibrosis and its end stage, cirrhosis, is a major public health problem worldwide. In western countries, prevailing causes of cirrhosis include chronic alcohol consumption, hepatitis C virus infection and non-alcoholic steatohepatitis. Current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Nevertheless, suppression of the cause of hepatic injury is not always feasible and numerous efforts are directed at the development of liver-specific antifibrotic therapies. Along these lines, the authors recently demonstrated that the endocannabinoid system shows promise as a novel target for antifibrotic therapy during chronic liver injury. Indeed, cannabinoid receptors CB1 and CB2 promote dual pro- and antifibrogenic effects, respectively. Therefore, endocannabinoid-based therapies, combining CB2 agonists and CB1 antagonists may open novel therapeutic perspectives for the treatment of chronic liver diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/17298297

[The endocannabinoid system as a novel target for the treatment of liver fibrosis].

Posted on by

Abstract

 “The cannabinoid system comprises specific G protein-coupled receptors (CB1 and CB2), exogenous (marijuana-derived cannabinoids) and endogenous (endocannabinoids) ligands, and a machinery dedicated to endocannabinoid synthesis and degradation. Studies over two decades have extensively documented the crucial role of the cannabinoid system in the regulation of a variety of pathophysiological conditions. However, its role in liver pathology has only been recently unravelled, probably given the low expression of CB1 and CB2 in the normal liver. We have recently demonstrated that CB1 and CB2 receptors display opposite effects in the regulation of liver fibrogenesis during chronic liver injury. Indeed, both receptors are up-regulated in the liver of cirrhotic patients, and expressed in liver fibrogenic cells. Moreover, CB1 receptors are profibrogenic and accordingly, the CB1 antagonist rimonabant reduces fibrosis progression in three experimental models. In keeping with these results, daily cannabis smoking is a risk factor for fibrosis progression in patients with chronic hepatitis C. In contrast, CB2 display antifibrogenic effects, by a mechanism involving reduction of liver fibrogenic cell accumulation. These results may offer new perspectives for the treatment of liver fibrosis, combining CB2 agonist and CB1 antagonist therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/17412522

Attenuation of Experimental Autoimmune Hepatitis by Exogenous and Endogenous Cannabinoids: Involvement of Regulatory T Cells

Posted on by

“The endocannabinoid system plays a protective role in various inflammatory diseases, and it is considered an attractive therapeutic target.”

“The aim of the present study was to determine the immunomodulatory effect of THC in the murine model of ConA-induced hepatitis. We demonstrate that a single injection of THC significantly ameliorates ConA-induced T-cell-mediated liver injury by up-regulating Forkhead helix transcription factor p3 (Foxp3)+ regulatory T cells and down-regulating inflammatory cytokines. Using select cannabinoid receptor agonists and antagonists, we demonstrate that THC mediates immune modulation in this model by signaling through both CB1 and CB2 receptors. We also demonstrate that anandamide, an endocannabinoid can effectively attenuate the disease.”

“There is growing interest in recent years to target cannabinoid receptors for treating liver diseases. In the current study, CB1 or CB2 activation alone had no anti-inflammatory effect on hepatitis. However, cannabinoids that bind to both CB1 and CB2 receptors (THC, CP55,940, WIN55212, and anandamide) effectively attenuated hepatitis. That CB1/CB2 mixed agonists could suppress the disease but not the coadministered CB1 and CB2 agonists indicates that both the cannabinoid receptors need to be activated simultaneously to produce the observed effect and that the different pharmacokinetics of the two coadministered agonists may not allow this to happen. Signaling through both the receptors is important because blocking either CB1 or CB2 could reverse the effect of THC.”

“Taken together, our data suggest that exogenous cannabinoids such as THC upon binding to CB1 and CB2 receptors on immune cells, induce apoptosis in effector T cells, up-regulate Treg function, and suppress inflammatory cytokines there by preventing ConA-induced activated T-cell-mediated liver injury. The observation that the anandamide treatment ameliorates ConA-induced hepatitis, together with FAAH deficiency or inhibition leading to increased resistance to the disease, strongly suggests that the endocannabinoid system serves to attenuate the inflammatory response in ConA-induced acute hepatitis. These findings raise the promising potential of developing novel pharmacological treatments for T-cell-mediated liver diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828293/

Association between lipid accumulation and the cannabinoid system in Huh7 cells expressing HCV genes.

Posted on by

Abstract

“Evidence from clinical and laboratory studies has accumulated indicating that the activation of the cannabinoid system is crucial for steatosis, especially in non-alcoholic fatty liver disease. However, the association between hepatitis C virus (HCV) infection and the cannabinoid system has not been well investigated and it is unclear whether steatosis in chronic hepatitis C develops via activation of the endocannabinoid/cannabinoid receptor signaling pathway. In this study, we examined the expression of a cannabinoid receptor (CB1) and the lipid accumulation in the hepatic Huh7 cell line, expressing HCV genes. We utilized Huh7/Rep-Feo-1b cells stably expressing HCV non-structural proteins (NS) 3, NS4, NS5A, and NS5B, as well as Tet-On Core-2 cells, in which the HCV core protein expression is inducible. Significantly higher levels of stored triglycerides were found in Huh7/Rep-Feo-1b cells compared to Huh7 cells. Also, triglyceride accumulation and CB1 receptor expression were down-regulated in Huh7/Rep-Feo-1b cells after HCV reduction by IFNα. Moreover, lipid accumulation appeared to increase after CB1 agonist treatment, while it decreased after CB1 antagonist treatment, although significant differences were not found compared to untreated cells. In Tet-On Core-2 cells, induction of HCV core protein expression did not affect CB1 expression or triglyceride accumulation. The results of this study in cultured cells suggest that HCV infection may activate the cannabinoid system and precede steatosis, but the core protein by itself may not have any effect on the cannabinoid system.”

http://www.ncbi.nlm.nih.gov/pubmed/21331443

Fatty acid amide hydrolase: a potential target for next generation therapeutics.

Posted on by

Abstract

“Endocannabinoids are amides, esters and ethers of long chain polyunsaturated fatty acids, which act as new lipid mediators. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of Delta(9)-tetrahydrocannabinol, the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA at its receptors is limited by cellular uptake through a specific membrane transporter, followed by intracellular degradation by a fatty acid amide hydrolase (FAAH). Growing evidence demonstrates that FAAH is the critical regulator of the endogenous levels of AEA, suggesting that it may serve as an attractive therapeutic target for the treatment of human disorders. In particular, FAAH inhibitors may be next generation therapeutic drugs of potential value for the treatment of pathologies in the central nervous system and in the periphery. Here, the potential applications of these inhibitors for human disease will be reviewed, with an emphasis on the properties of hydro(pero)xy-anandamides. In fact, these oxygenated derivatives of AEA are the most powerful inhibitors of FAAH of natural origin as yet discovered. In addition, new insights into the promoter region of FAAH gene will be presented, and the therapeutic potential of mimetics of transcription factors of this gene in the management of human infertility will be discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/16472164

Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system.

Posted on by

Abstract

“The family of endocannabinoids contains several polyunsaturated fatty acid amides such as anandamide (AEA), but also esters such as 2-arachidonoylglycerol (2-AG). These compounds are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of Delta9-tetrahydrocannabinol (Delta9-THC), the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA at its receptors is limited by cellular uptake, through a putative membrane transporter, followed by intracellular degradation by fatty acid amide hydrolase (FAAH). Growing evidence demonstrates that FAAH is the critical regulator of the endogenous levels of AEA, suggesting that it may serve as an attractive therapeutic target for the treatment of human disorders. In particular, FAAH inhibitors may be next generation therapeutics of potential value for the treatment of pathologies of the central nervous system, and of peripheral tissues. Investigations into the structure and function of FAAH, its biological and therapeutic implications, as well as a description of different families of FAAH inhibitors, are the topic of this chapter.”

http://www.ncbi.nlm.nih.gov/pubmed/18751909

Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma.

Posted on by

“Anaplastic thyroid carcinoma is the most aggressive type of thyroid malignancies…”

 “These data suggest that CB2 overexpression may contribute to the regression of human anaplastic thyroid tumor… Given that cannabinoids have shown antitumor effects in many types of cancer models, CB2 may be a viable therapeutic target for the treatment of anaplastic thyroid carcinoma.”

http://www.ncbi.nlm.nih.gov/pubmed/18197164

Inhibition of Human Neutrophil Chemotaxis by Endogenous Cannabinoids and Phytocannabinoids: Evidence for a Site Distinct from CB1 and CB2

Posted on by

   “Here, we show a novel pharmacology for inhibition of human neutrophil migration by endocannabinoids, phytocannabinoids, and related compounds. The endocannabinoids virodhamine and N-arachidonoyl dopamine are potent inhibitors of N-formyl-l-methionyl-l-leucyl-l-phenylalanine-induced migration of human neutrophils…”

   “This study reveals that certain endogenous lipids, phytocannabinoids and related ligands are potent inhibitors of human neutrophil migration, and it implicates a novel pharmacological target distinct from cannabinoid CB1 and CB2 receptors; this target is antagonized by the endogenous compound N-arachidoloyl l-serine. These findings corroborate the emerging clinical and animal model data demonstrating that the nonpsychoactive phytocannabinoid, CBD and its structural analogs are effective in alleviating arthritis. Furthermore, our findings have implications for the potential pharmacological manipulation of elements of the endocannabinoid system for the treatment of various inflammatory conditions.”

http://molpharm.aspetjournals.org/content/73/2/441.long

Fungal biotransformation of cannabinoids: potential for new effective drugs.

Posted on by

Abstract

“Phytocannabinoids from the plant Cannabis sativa induce a variety of physiological and pharmacological responses in living systems, including anti-inflammatory, antinociceptive, anti-ulcer and antitumor activities. The discovery of the cannabinoid receptors CB1 and CB2 led to the development of agonists and antagonists of these receptors for the treatment of a variety of diseases. Nabilone, a synthetic derivative of Delta9-tetrahydrocannabinol (Delta9-THC), which is the main natural psychotropic constituent of C sativa, was approved by the US FDA for the treatment of nausea and as an anti-emetic for patients undergoing chemotherapy. Delta9-THC and related cannabinoids are involved in a variety of signal transduction pathways; thus, reducing or removing the psychotropic effects of these compounds would enhance their therapeutic spectra. Compound synthesis and qualitative SAR studies are time-consuming activities; however, microbes are effectively the most inventive synthetic chemists because of their metabolic plasticity. This review discusses the potential of C sativa mycoflora, which is pathogenic as well as endophytic, to remove the psychotropic effects of Delta9-THC and related cannabinoids, and describes the development of a model system for the rapid and cost-effective commercial production of cannabinoids through fermentation pathways.”

http://www.ncbi.nlm.nih.gov/pubmed/19333876

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1.

Posted on by

Cover image

“Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls.

Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.”  http://www.ncbi.nlm.nih.gov/pubmed/19914218

http://www.sciencedirect.com/science/article/pii/S000629520900971X