The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings

Abstract

Chronic liver diseases represent a major health problem due to cirrhosis and its complications. During the last decade, endocannabinoids and their receptors have emerged as major regulators of several pathophysiological aspects associated with chronic liver disease progression. Hence, hepatic cannabinoid receptor 2 (CB2) receptors display beneficial effects on alcoholic fatty liver, hepatic inflammation, liver injury, regeneration and fibrosis. Cannabinoid receptor 1 (CB1) receptors have been implicated in the pathogenesis of several lesions such as alcoholic and metabolic steatosis, liver fibrogenesis, or circulatory failure associated with cirrhosis. Although the development of CB1 antagonists has recently been suspended due to the high incidence of central side effects, preliminary preclinical data obtained with peripherally restricted CB1 antagonists give real hopes in the development of active CB1 molecules devoid of central adverse effects. CB2‐selective molecules may also offer novel perspectives for the treatment of liver diseases, and their clinical development is clearly awaited. Whether combined treatment with a peripherally restricted CB1 antagonist and a CB2 agonist might result in an increased therapeutic potential will warrant further investigation. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…CB1 stimulation of mouse and rat liver regeneration was reported (595,686), although CB1 may also promote hepatocellular carcinoma initiation and progression (596). Indeed, the ECS has emerged as either one of the causes or a negative modulator of most pathological aspects associated with chronic liver disease progression (525). Liver injury is associated with increased endocannabinoid tone, with AEA being produced by hepatocytes, Kupffer cells, and endothelial cells and 2-AG by hepatic stellate cells and hepatocytes (49, 525).…”

“…Consequently, the genetic or pharmacological blockade of this pathway protects mice from liver injury also via non-cannabinoid receptor-mediated mechanisms (114). In liver injury, CB2 may become upregulated in Kupffer cells and hepatic myofibroblasts, and CB1 in hepatocytes, hepatic myofibroblasts, and endothelial cells (525).…”

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

“…One other adjunctive strategy for a cannabinoid receptor agonist may be to administer it together with a CB 1 receptor antagonist/inverse agonist. Thus, for example, it has been found that -an ultra-low dose of SR141716A can prolong R-(þ)-WIN55212-induced antinociception in a rat model of acute pain [113]; -an ultra-low dose of AM251 can enhance the ability of the CB 1 -selective agonist, arachidonyl-2 0 -chloroethylamide, to protect mice from pentylenetetrazole-induced seizures [114]; and -administration of a selective CB 1 receptor antagonist/inverse agonist together with a CB 2 -selective agonist may be particularly effective for the treatment of hepatic ischaemia/reperfusion injury caused by liver transplantation [115] and of disorders, such as Parkinson's disease [116], systemic sclerosis [117], chronic liver diseases, including alcohol-induced liver injury [56] and stroke [118], and perhaps also for the management of cocaine dependence [45,119].…”

Sistema endocanabinoide y desarrollo de esteatosis hepática

“…Sin embargo, el daño hepático en distintos grados está asociado a un aumento de la expresión de RCB 1 en hepatocitos, miofibroblastos y células endoteliales y de RCB 2 en células de Kupffer y miofibroblastos 1 . Adicionalmente, en respuesta a daño hepático agudo o crónico hay un aumento de la concentración de 2-AG en hepatocitos y en células estrelladas, y de ADA en hepatocitos, células endoteliales y de Kupffer 11,13,14 . Estos antecedentes indican la existencia de un mayor tono endocanabinoide hepá-tico en condiciones fisiopatológicas, tales como la esteatosis alcohólica y no alcohólica.…”