The endocannabinoid system in advanced liver cirrhosis: pathophysiological implication and future perspectives

Abstract

Endogenous cannabinoids (EC) are ubiquitous lipid signalling molecules providing different central and peripheral effects that are mediated mostly by the specific receptors CB1 and CB2. The EC system is highly upregulated during chronic liver disease and consistent experimental and clinical findings indicate that it plays a role in the pathogenesis of liver fibrosis and fatty liver disease associated with obesity, alcohol abuse and hepatitis C. Furthermore, a considerable number of studies have shown that EC and their receptors contribute to the pathogenesis of the cardio-circulatory disturbances occurring in advanced cirrhosis, such as portal hypertension, hyperdynamic circulatory syndrome and cirrhotic cardiomyopathy. More recently, the EC system has been implicated in the development of ascites, hepatic encephalopathy and the inflammatory response related to bacterial infection. Rimonabant, a selective CB1 antagonist, was the first drug acting on the EC system approved for the treatment of obesity. Unfortunately, it has been withdrawn from the market because of its neuropsychiatric side effects. Compounds able to target selectively the peripheral CB1 receptors are under evaluation. In addition, molecules stimulating CB2 receptor or modulating the activity of enzymes implicated in EC metabolism are promising areas of pharmacological research. Liver cirrhosis and the related complications represent an important target for the clinical application of these compounds.

Alteration of intrahepatic microcirculation in cirrhotic livers

“…70,71 The same study also observed an inhibition of the activated hepatic endocannabinoid system in ciprofloxacin-treated cirrhotic animals, which enhanced the concepts of endotoxemia and activate hepatic endocannabinoid system in cirrhosis. 11,58,70 Actually, chronic administration of the cannabinoid receptor antagonist inhibits the hepatic inflammation and fibrogenesis in cirrhotic animals. 9,63 However, increased hepatic endocannabinoid production enhanced the hepatic vasoconstrictive response to ET-1 and subsequently increased IHR and portal hypertension in nonalcoholic steatohepatitis (NASH)-cirrhotic rats.…”

“…cirrhosis. 11,58,70 HED is characterized by an increased pressure response to vasoconstrictors including endocannabinoids in hepatic microvasculatures. 40,41,48,49 Chronic administration of ciprofloxacin had also been found to inhibit endotoxemia, improve HED, and decrease IHR in cirrhotic animals.…”

New therapies for hepatic fibrosis

“…CB1 agonists activate hepatic stellate cells to myofibroblasts. CB1 receptor agonists, such as Rimonabant, inhibit and reverse experimental liver fibrosis [43][44]. A peripherally acting CB1 antagonist could treat liver fibrosis without inducing depression.…”

Molecular Mechanisms Leading to Splanchnic Vasodilation in Liver Cirrhosis

“…Apart from CB1, other receptors, such as TRPV1, may be implicated in the EC-dependent vasorelaxation of liver cirrhosis. TRPV1, expressed in perivascular nerves, has been shown to mediate the hypotensive effect of EC in cirrhosis [65]. Moreover, it has been shown that in cirrhotic rats pretreatment with a molecule blocking the response of sensory nerves impairs the mesenteric artery vasorelaxation induced by anandamide, suggesting that the signaling pathway leading to relaxation is located in the adventitia of the vessels, where primary sensory nerves are situated.…”