Tag Archives: liver

Antagonism of the cannabinoid CB-1 receptor protects rat liver against ischaemia-reperfusion injury complicated by endotoxaemia.

Posted on by
Reply

  “Endotoxaemia can complicate hepatic ischaemia-reperfusion (IR) injury. Endocannabinoids appear to modulate the haemodynamic alterations and cytokine response induced by lipopolysaccharide (LPS). Thus, we aimed to determine the effect of the endocannabinoid CB1-receptor antagonist Rimonabant in a model of hepatic IR injury complicated by endotoxaemia.”

“Liver injury and neutrophil infiltration occurring in the late-phase of LPS-enhanced IR were significantly reduced by CB1-receptor antagonism.”

“CONCLUSIONS:

This study demonstrates that CB1-receptor antagonism protects the liver against LPS-enhanced IR injury by interfering with the inflammatory response that causes the late, neutrophil-dependent phase of reperfusion injury, although the prevention of the transient endotoxin-related hypotension occurring early during reperfusion may be also involved.”

http://www.ncbi.nlm.nih.gov/pubmed/19282305

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

Posted on by
Reply

  “Alcohol abuse, viral hepatitis and non-alcoholic fatty liver disease (NAFLD) represent the major causes of chronic liver injury, resulting in progressive accumulation of fibrosis within the liver parenchyma. Progression to cirrhosis exposes patients to life-threatening complications of portal hypertension liver failure and hepatic encephalopathy, and to a high risk of developing hepatocellular carcinoma. Overall, chronic liver diseases represent a major health problem with an estimated rate of death in the range of 1 400 000 per year worldwide. Recent findings have revealed a role of endocannabinoids and their receptors in the pathogenesis of several key steps of acute and chronic liver injury, therefore identifying pharmacological modulation of cannabinoid receptors as an attractive strategy for the management of morbidity related to liver injury .”

 

“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.”

 

“Cannabis Sativa has a long-standing history of recreational and therapeutic use, starting over 200 years ago. Understanding of pathways involved in the pharmacological properties of cannabinoids has only emerged with the identification of an endocannabinoid system that comprises at least two specific G-protein coupled receptors [cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)], their endogenous lipidic ligands (endocannabinoids), and enzymes involved in endocannabinoid synthesis and degradation.”

“Over the past 10 years, the endocannabinoid system has emerged as a major player in the pathogenesis of liver diseases. CB1 receptors have been implicated in the pathogenesis of several lesions such as liver fibrogenesis, alcoholic and metabolic steatosis, or circulatory failure associated with cirrhosis. In contrast, stimulation of hepatic CB2 receptors is emerging as an overall protective pathway with antifibrogenic properties and beneficial effects on liver inflammation, alcoholic fatty liver and hepatocyte survival and regeneration. Exciting therapeutic developments expected with the availability of CB1 receptor antagonists have been put to a hold, due to the high incidence of central side effects of first generation compounds. Fortunately, CB1 antagonists devoid of brain penetrance are increasingly being synthetized and initial results suggest that they exhibit beneficial effects expected from previous studies. The clinical development of CB2-selective agonists is also eagerly awaited.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165953/

Endocannabinoids as novel mediators of liver diseases.

Posted on by
Reply

Abstract

“In the past two decades, cannabinoids have emerged as crucial mediators in a variety of pathophysiological conditions. Awareness of their critical functions in liver pathophysiology is only recent, probably given the low level of expression of cannabinoid receptor type 1 (CB1 receptor) and type 2 (CB2 receptor) in normal liver. However, it has been shown that non-alcoholic fatty liver disease and cirrhosis are associated to a marked upregulation of the hepatic endocannabinoid system, including increases in endocannabinoids and in hepatic CB receptors, both in humans and in rodents. Consequently, a growing number of cannabinoid-related hepatic effects are being unravelled. Hence, hepatic CB1 receptors enhance liver steatogenesis in a mouse model of high fat-induced obesity, and contribute to peripheral arterial vasodilation in cirrhosis, thereby promoting portal hypertension. In addition, CB1 and CB2 receptors elicit dual opposite effects on fibrogenesis associated to chronic liver injury, by promoting pro- and antifibrogenic effects, respectively. Therefore, endocannabinoid-based therapies may open novel therapeutic avenues in the treatment of chronic liver diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/16751709

Endocannabinoids in Liver Disease.

Posted on by
Reply

“Marijuana has been used for its psychoactive and medicinal properties for millennia. As other plant-derived substances, marijuana has been slow to yield its secrets, with insights into its mechanism of action beginning to emerge only during the last decades. The existence of specific CB receptors in mammalian tissues was first revealed by radioligand binding, followed by the molecular cloning of two G protein-coupled cannabinoid receptors (1). CB1 receptors are the most abundant receptors in the mammalian brain, but are also expressed in peripheral tissues, including various cell types of the liver, at much lower yet functionally relevant concentrations. CB2 receptors are expressed primarily in immune and hematopoietic cells, and have also been detected in the liver in certain pathological states. Additional CB receptors may exist…”

“Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and is present both in brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases, which contributes to the underlying pathologies. In cirrhosis of various etiologies, activation of vascular and cardiac CB1 receptors by macrophage- and platelet-derived endocannabinoids contribute to the vasodilated state and cardiomyopathy, which can be reversed by CB1 blockade. In mouse models of liver fibrosis, activation of CB1 receptors on hepatic stellate cells is fibrogenic, and CB1 blockade slows the progression of fibrosis. Fatty liver induced by high-fat diets or chronic alcohol feeding depend on activation of peripheral, including hepatic CB1 receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB1 blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB1 antagonists.”

“Concluding Remarks

The ECS is present in the liver and is involved in the control of various hepatic functions with important therapeutic implications. Increased CB1 activity contributes to the hemodynamic abnormalities and promotes fibrosis in liver cirrhosis, whereas CB1 blockade attenuates and delays these changes. Endocannabinoids acting via hepatic CB1 receptors have emerged as mediators of both diet-induced and alcoholic fatty liver which, together, account for the majority of cirrhosis in Western societies. Additionally, hepatic CB1 activation contributes to obesity-related insulin- and leptin-resistance and dyslipidemias. This provides strong rationale for the therapeutic use of CB1 antagonists in these conditions. Although neuropsychiatric side effects limit the therapeutic potential of brain-penetrant CB1 antagonists, the recent emergence of second generation, peripherally-restricted CB1 antagonists may mitigate this problem. Additionally, non-psychoactive CB2 agonists may offer therapeutic benefit in attenuating liver injury and promoting tissue repair in the fibrotic liver.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073545/

Endocannabinoids and Liver Disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases

Posted on by
Reply

  “Recent studies have implicated dysregulation of the endocannabinoid system in various liver diseases and their complications (e.g., hepatitis, fibrosis, cirrhosis, cirrhotic cardiomyopathy, and ischemia-reper-fusion), and demonstrated that its modulation by either cannabinoid 2 (CB2) receptor agonists or CB1 antagonists may be of significant therapeutic benefits. This review is aimed to focus on the triggers and sources of endocannabinoids during liver inflammation and on the novel role of CB2 receptors in the interplay between the activated endothelium and various inflammatory cells (leukocytes, lymphocytes, etc.), which play pivotal role in the early development and progression of inflammatory and other liver diseases.”

“Dysregulation of the endocannabinoid system (ECS) has been implicated in virtually all diseases affecting humans, and its pharmacological modulation holds tremendous promise in the treatment of pain, cancer, and metabolic, cardiovascular, and various inflammatory disorders. Numerous recent studies have linked dysregulation of the ECS to a number of liver diseases including hepatitis, nonalcoholic fatty liver disease, hepatic ischemia-reperfusion (I/R) injury, and liver fibrosis and cirrhosis and its hemo-dynamic consequences. In aggregate these studies have suggested that modulation of the ECS by either CB1 antagonists or CB2 receptor agonists may be of significant therapeutic benefit. This synopsis will focus on sources and triggers of endocannabinoids during liver inflammatory disorders (in both leukocytes and parenchymal cells) and on the novel role of CB2 receptors in the interplay between inflammatory cells and the activated endothelium, which plays a crucial role in the early development and progression of inflammatory liver diseases”.

“Collectively, the studies discussed above emphasize the potential immunoregulatory role of the endocannabinoid system in a variety of inflammatory liver disorders, opening new avenues for their pharmacotherapy. There is considerable interest in the development of selective CB2 receptor agonists, which are devoid of psychoactive properties of CB1 agonists, for various inflammatory disorders. Selective CB2 cannabinoid agonists may protect against hepatic inflammatory disorders by attenuating the endothelial cell activation/inflammatory response (e.g., the expression of adhesion molecules, release of chemotactic factors, inflammatory mediators, etc.) and by decreasing the migration and the adhesion of inflammatory cells to the endothelium, transendothelial migration, adhesion to parenchymal cells and activation, and interrelated oxidativenitrosative stress-inflammatory response. It appears that CB1 antagonists might be beneficial in slowing the progression of liver fibrosis and the neurological decline associated with hepatic encephalopathy, in addition to the attenuation of the adverse hemodynamic consequences of cirrhosis, thus extending life until a suitable liver becomes available for transplantation. CB1 antagonists may also be useful in the treatment of obesity-associated liver diseases and related features of metabolic syndrome by improving dyslipidemia and attenuating systemic and liver inflammation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376822/

Endocannabinoids and Liver Disease. I. Endocannabinoids and their receptors in the liver

Posted on by
Reply

  “The medicinal properties of cannabis (Cannabis sativa, marijuana) have been known for millennia, as shown by reports from China and India underscoring its analgesic, antiemetic, and appetite-stimulating properties. During the 19th century, the prescription of cannabis gained popularity for a variety of conditions ranging from epilepsy to rheumatism and abdominal symptoms. Concerns about abuse led to discontinuation of therapeutic use in the 1940s. The characterization of marijuana-derived bioactive molecules began during the early 20th century with the identification of several hydrophobic compounds and culminated in 1964 with the isolation of Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of the plant. Subsequent studies identified over 60 other phytocannabinoids and allowed the synthesis of active analogs with varying potencies. This step was critical in the identification of the endocannabinoid system, comprising specific cannabinoid binding sites (CB1 and CB2), their endogenous ligands (endocannabinoids), and synthetic and degradative pathways.”

“Cannabinoid receptors (CB1 and CB2) and their endogenous ligands (endocannabinoids) have recently emerged as novel mediators of liver diseases. Endogenous activation of CB1 receptors promotes nonalcoholic fatty liver disease (NAFLD) and progression of liver fibrosis associated with chronic liver injury; in addition, CB1 receptors contribute to the pathogenesis of portal hypertension and cirrhotic cardiomyopathy. CB2 receptor-dependent effects are also increasingly characterized, including antifibrogenic effects and regulation of liver inflammation during ischemia-reperfusion and NAFLD. It is likely that the next few years will allow us to delineate whether molecules targeting CB1 and CB2 receptors are useful therapeutic agents for the treatment of chronic liver diseases.”

http://ajpgi.physiology.org/content/294/1/G9.long

The role of the endocannabinoid system in liver diseases.

Posted on by
Reply

Abstract

“Endogenous cannabinoids (ECs) are ubiquitous lipid signaling molecules provided by a number of central and peripheral effects, which are mediated mainly by the specific receptors CB1 and CB2. In the last decade a considerable number of studies has shown that ECs and their receptors play an important role in the pathophysiology of liver diseases. The EC system is strongly up-regulated during chronic liver diseases. Until now it has been implicated in the pathogenesis of fatty liver disease associated with obesity, alcohol abuse, and hepatitis C, in the progression of fibrosis to cirrhosis, and in the development of portal hypertension, hyperdynamic circulatory syndrome and its complications, and cirrhotic cardiomyopathy. Furthermore, the EC system can participate in the pathogenesis of acute liver injury by modulating the mechanisms responsible for cell injury and inflammatory response. Thus, targeting the CB1 and CB2 receptors represents a potential therapeutic goal for the treatment of liver diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/19285261