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07-20-2012, 11:58 AM
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Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects
A A Izzo1, M Camilleri2
1 Department of Experimental Pharmacology, University of Naples Federico II and Endocannabinoid Research Group, Naples, Italy
2 Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
Correspondence to:
Professor A A Izzo, Department of Experimental Pharmacology, University of Naples Federico II, via D Montesano 49, 80131, Naples, Italy; aaizzo@unina.it
ABSTRACT
A multitude of physiological effects and putative pathophysiological roles have been proposed for the endogenous cannabinoid system in the gastrointestinal tract, liver and pancreas. These range from effects on epithelial growth and regeneration, immune function, motor function, appetite control, fibrogenesis and secretion. Cannabinoids have the potential for therapeutic application in gut and liver diseases. Two exciting therapeutic applications in the area of reversing hepatic fibrosis as well as antineoplastic effects may have a significant impact in these diseases. This review critically appraises the experimental and clinical evidence supporting the clinical application of cannabinoid receptor-based drugs in gastrointestinal, liver and pancreatic diseases. Application of modern pharmacological principles will most probably expand the selective modulation of the cannabinoid system peripherally in humans. We anticipate that, in addition to the approval in several countries of the CB1 antagonist, rimonabant, for the treatment of obesity and associated metabolic dysfunctions, other cannabinoid modulators are likely to have an impact on human disease in the future, including hepatic fibrosis and neoplasia.
SOURCE: http://gut.bmj.com/c...tract/57/8/1140
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<strong>Cannabinoid 1 and Ulcerative Colitis and the Phenotype in Crohn's Disease </strong>
The Cannabinoid 1 Receptor (CNR1) 1359 G/A Polymorphism Modulates Susceptibility to Ulcerative Colitis and the Phenotype in Crohn's Disease
Martin Storr,1* Dominik Emmerdinger,2 Julia Diegelmann,2 Simone Pfennig,2 Thomas Ochsenkhn,2 Burkhard Gke,2 Peter Lohse,3 and Stephan Brand2
1Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
2Department of Medicine II Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany
3Department of Clinical Chemistry Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany
Syed A. Aziz, Editor
Health Canada, Canada
* E-mail: mstorr@ucalgary.ca
Conceived and designed the experiments: MS JD TO BG PL SB. Performed the experiments: DE. Analyzed the data: MS DE JD SP PL SB. Contributed reagents/materials/analysis tools: MS TO BG PL. Wrote the paper: MS SB.
Received January 15, 2010; Accepted January 27, 2010.
This article has been cited by other articles in PMC.
Abstract
Background
Recent evidence suggests a crucial role of the endocannabinoid system, including the cannabinoid 1 receptor (CNR1), in intestinal inflammation. We therefore investigated the influence of the CNR1 1359 G/A (p.Thr453Thr; rs1049353) single nucleotide polymorphism (SNP) on disease susceptibility and phenotype in patients with ulcerative colitis (UC) and Crohn's disease (CD).
Methods
Genomic DNA from 579 phenotypically well-characterized individuals was analyzed for the CNR1 1359 G/A SNP. Amongst these were 166 patients with UC, 216 patients with CD, and 197 healthy controls.
Results
Compared to healthy controls, subjects A/A homozygous for the CNR1 1359 G/A SNP had a reduced risk to develop UC (p=0.01, OR 0.30, 95% CI 0.120.78). The polymorphism did not modulate CD susceptibility, but carriers of the minor A allele had a lower body mass index than G/G wildtype carriers (p=0.0005). In addition, homozygous carriers of the G allele were more likely to develop CD before 40 years of age (p=5.9107) than carriers of the A allele.
Conclusion
The CNR1 p.Thr453Thr polymorphism appears to modulate UC susceptibility and the CD phenotype. The endocannabinoid system may influence the manifestation of inflammatory bowel diseases, suggesting endocannabinoids as potential target for future therapies.
Introduction
Anecdotal reports suggest that marijuana- or tetrahydrocannabinol-containing products may be effective in alleviating symptoms in patients with ulcerative colitis (UC) and Crohn's disease (CD). [1], [2] This is supported by recent studies of our group and others suggesting that pharmacological activation of the cannabinoid 1 (CB1) receptor with selective receptor agonists decreases the inflammatory response in various murine models of colonic inflammation including dinitrobenzene sulphonic acid (DNBS)-, trinitrobenzene sulphonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colitis. [3][7]
Interestingly, pharmacological blockade of CB1 receptors or genetic ablation of CB1 receptors (CNR1/ mice) aggravates intestinal inflammation in these models, [3], [7] emphasizing the physiological relevance of the CB1 receptor in the protection against intestinal inflammation. Increased mucosal levels of the endocannabinoid anandamide during intestinal inflammation in humans further stress the role of the CB1 receptor and the endocannabinoid system in intestinal inflammation. [4] Thus, present knowledge suggests up-regulation of endocannabinoids as an important protective mechanism in intestinal inflammation.
The endocannabinoid system and the CB1 and CB2 receptors seem to be crucially involved in the regulation of multiple physiological functions, e.g. in the heart, where they relax coronary arteries and decrease cardiac work, [8] in organ perfusion, [9] in metabolic homeostasis, [10], [11] and in the regulation of bone mass by osteoclasts, [12] as well as in the protection against stress responses, inflammation, and associated repair mechanisms. [13], [14] Although recent evidence suggests that the endocannabinoid system is involved in many physiological and pathophysiological functions of the gastrointestinal tract such as intestinal motility, secretion, and intestinal inflammation [3], [15][20], the exact mechanisms underlying these findings are not yet known. It was recently suggested that CB1 signaling may be up-regulated during colitis, [3] but it is unknown whether this is a specific feature of the colitis model or a general response to intestinal inflammation.
Moreover, the role of the CB1 receptor in human inflammatory bowel disease (IBD) has not been clarified. Increased anandamide levels were found in mucosal biopsies from UC patients, suggesting a role of the endocannabinoid system in UC. [4] In contrast, the colonic exp<b></b>ression of the endocannabinoid 2-acyl-glycerol (2-AG) is not increased in UC. [4] So far, however, no other studies analyzing the endocannabinoid system or the pharmacological effects of cannabinoids in human IBD have been published.
Gastrointestinal inflammation is likely the result of multiple factors, e.g., increased pro-inflammatory stimuli and reduced protective capability. The overall balance between pro- and anti-inflammatory mechanisms may determine the progression and severity of intestinal inflammation. [21], [22] Given the results of recent genome-wide association studies, [23] genetic susceptibility is an important factor contributing to IBD development. Moreover, knowledge of genetic susceptibility factors could provide important pathophysiologic insights for the generation of novel IBD therapeutics.
Considering our previous work on the endocannabinoid system in murine intestinal inflammation, [3], [6], [7], [24] we hypothesized that genetic variants in the CNR1 gene, which may modulate CB1 receptor function, could be associated with an increased susceptibility to IBD. To test our hypothesis, we genotyped a cohort of more than 550 individuals including 382 IBD patients and analyzed whether the 1359 G/A (p.Thr453Thr; rs1049353) single nucleotide polymorphism (SNP) within the CNR1 gene encoding the CB1 receptor modulates the susceptibility to CD and UC or results in a certain IBD phenotype. The selection of the CNR1 1359 G/A SNP was based on previous studies reporting that this polymorphism is associated with other disorders modulated by the endocannabinoid system such as alcohol dependence and hebephrenic schizophrenia. [25], [26]
Methods
<strong>Cannabinoids ameliorate cerebral dysfunction following liver failure </strong><strong>via</strong><strong> AMP-activated protein kinase </strong>
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We studied the etiology of cerebral dysfunction in a murine model of HE induced by either bile duct ligation or thioacetamide administration. We report that stimulation of cerebral AMP-activated protein kinase (AMPK), a major intracellular energy sensor, is a compensatory response to liver failure. This function of AMPK is regulated by endocannabinoids. The cannabinoid system controls systemic energy balance via the cannabinoid receptors CB-1 and CB-2. Under normal circumstances, AMPK activity is mediated by CB-1 while CB-2 is barely detected. However, CB-2 is strongly stimulated in response to liver failure. Administration of 9-tetrahydrocannabinol (THC) augmented AMPK activity and restored brain function in WT mice but not in their CB-2 KO littermates. These results suggest that HE is a disease of energy flux. CB-2 signaling is a cerebral stress response mechanism and makes AMPK a promising target for its treatment by modulating the cannabinoid system.Dagon, Y., Avraham, Y., Ilan, Y., Mechoulam, R., Berry, E. M. Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase.
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