4) ARTICLE - endocannabinoids [2011.10.15]

The actions of endocannabinoids at a peripheral and central level
Endocannabinoids, liver disease, central nervous system,
metabolic syndrome, insulin-resistance

Endocannabinoids are found in the central nervous system and in the liver, and are involved in the control of different hepatic and metabolic functions. They play a role in hemodynamic alterations, in the control of fibrosis, and in the progression of NAFLD and NASH. They also regulate insulin-resistance, leptin-resistance, and metabolic syndrome. CB1 antagonists regulate hunger and weight, and reduce hepatic damage by stimulating tissue repair. CB2 agonists determine a reduced response to damage and a reduction of fibrosis in cirrhosis.
The study of endocannabinoids has recently been able to correlate them with hepatic pathologies typical of major dysmetabolisms.
From a metabolic point of view their action takes place mainly at a peripheral level. The activation of CB1 is related with the progression of hepatic fibrosis typical of chronic liver damage, and contributes to portal hypertension and chirrotic cardiomiopathy. CB2 seems to be associated with anti-fibrogenic effects and the regulation of phlogosis in NAFLD, mainly in regulating ischemia-reperfusion damage.
Moreover endocannabinoids act on the central nervous system having as target its metabolism regulators.
The aim of this study is to obtain elements of physio-pathological logic that will permit the introduction of new agents for the treatment of chronic liver pathologies.
Endocannabinoids are bioactive lipids capable of linkage with cannabinoid receptors.
In order of discovery, they are:
- arachidonoil etanolamide, anandamide – AEA – discovered in 1992
- 2-arachidonoilglicerolo – 2AG – discovered in 1995
- 2-arachidonil-gliceril-ether – 2-AGE – a structural analogue of 2AG
- oleil-etanolamine – OEA
- virodamine
- N-arachidonoildopamine – NADA
- palmitoil-etanolamine – PEA
Endocannabinoids are not stored in vesicles, but rather synthesized ‘on demand’ starting from membrane phosphor-lipidic precursors. The biosynthesis begins with stimulus that triggers the depolarization of cell membrane. After synthesis they are immediately released from the cell and link cannabinoids receptors on nearby cells or on the same cell that produced them, and therefore with autocrine or paracrine action. Sometimes they behave as retrogradous messengers: they are synthesized in postsynaptic cells, and then go to activate CB1 receptors of the axons in presynaptic cells.
After exerting their action, the endocannabinoids are degraded or go through other processes such as: recaptation by passive diffusion through the membrane, hydrolysis, or the re-use of degraded products.
Endocannabinoids are expressed mainly in the liver, of which they regulate physiology, and of different physio-pathological grades typical of metabolic pathologies (already made and dating back to central mechanisms) ranging from the generic metabolic syndrome to more specific pictures of steatosis, NAFLD (non alcoholic fatty liver disease), NASH (non alcoholic steato-hepatitis), and situations of fibrosis-cirrhosis typical of advanced phases of liver injuries.
They are particularly present in different cells in association with different pathological conditions [1]:
- in hepatocyte we find
o CB1 – associated with CBP, primitive biliar cirrhosis, diet steatosis, and alcoholic steatosis
o CB2 – associated with CBP, regeneration, steatosis, and NASH
- in colangiocyte we find
o CB1 – associated with cirrhosis and portal hypertension
o CB2 – associated with CBP, and NAFLD
Endocannabinoids have the following functions [2]:
- they have an anti-stress function similar to endorphins, at both central and peripheral level
- they are produced in order to protect the organism thanks to an anti-oxidative action [3]
- they have an analgesic activity [4] [5] [6] [7] [8]
- they have a vaso-dilatory and hypotension action, with a physio-pathological role that must still be investigated further [9] [10] [11]
- they have a role in modulating immune system response [12] [13] [14]
- they regulate the cellular proliferation processes that lie at the basis of tumor growth [15]
- they are involved in steatosis pathogenesis [16]
- they are involved in obesity pathogenesis [16]
- they determine the progression from fibrosis to cirrhosis in the liver [16]
- they have a role in hyper-dynamic circulation syndrome [16]
- they are related to sodium retention and ascites formation
- they are up-regulated in hepato-carcinome
In further detail, other metabolic effects are receptor-specific [2]:
- insulin-resistance
- dislipidemia
- contribution to the onset of hepatic steatosis by excessively fat diets or by chronic alcoholism
- NAFLD promotion
- progression of hepatic fibrosis, with action of stellate cells
- condition of vasodilatation
- pathogenesis of portal hypertension
- pathogenesis of cirrhotic cardiomiopathy
by blocking CB1 (for example with rimonabant) which produces:
- prevention of steatosis
- slowdown of progression of fibrosis
- remission of cirrhotic cardiomiopathy
- reduction of portal hypertension
- anti-inflammatory effects
- anti-fibrogenetic effects
- regulation of hepatic inflammation during ischemia-reperfusion in NAFLD
in regard to their alterations at a serum level, the following have been found:
- a high level of OEA, PEA in cirrhosis [17]
- an expression of anandamide and 2-AG in hepatic ischemia-reperfusion damage [18]
Analyzing the variations in association with the pathologies permits the definition of:
- metabolic syndrome – CB1 is a mediator of the sensation of hunger, and CB1 antagonists have been hypothesized in obesity therapy such as rimonabant [19]: the loss of weight is due to reduced food absorption and reduced lipogenesis
- adiponectin – a CB1 blockade determines an increase in this adipokine, with positive effects on weight and metabolic syndrome [20]
- insulin-resistance – AM6545, CB1 antagonist, determines a reduction of insulin-resistance and leptin-resistance [19]; furthermore a CB1 block determines the captation of glucose thanks to insulinic stimulation, on the contrary activated CB1 triggers glucidic intolerance
- steatosis – CB1-/- deleted rats are resistant to alcohol steatosis
- ischemia-reperfusion damage – a CB1 blockade determines a reduction of both damage and endotoxiemia
- CBP – a hyper-regulation of the cannabinoid system has been seen in primitive biliar cirrhosis, mainly expressed in hepatocytes, in the cells of biliar epitelium, and in Kupffer cells; it has also been shown how proliferant colangiocytes constitute the “neuro-endocrine compartment” of the liver, able to secrete numerous substances among which endocannabinoids; the peripheral subministration of a selective CB1 agonist (HU210) reduces pruritus induced by histamine, and mitigates the excitation of cutaneous neural fibers (with the anti-nociceptive action related to opioids) [21]
- NASH – it has been viewed an hyper-expression of the CB2 receptor at the cytoplasmic level of hepatocytes, colangiocytes, and stellate cells [22]
- hepatic fibrosis – THC, tetraidrocannabinol, derived from marijuana is capable of linking CB1 and CB2 receptors, and is anti-fibrotic and hepatoprotector [23]
- cirrhosis – in cirrhosis there is an increase in CBs, which has mainly been viewed an increase in CB1 in perivascular nervous fibers of resistance mesenteric arteries [24]; haemodynamic alterations associated with CB1, that determines hypotension and endotoxic shock; in particular it has been shown that in this pathology there is a rise in CB1 in endothelial cells mainly in mesenteric arteries. Moreover an increase in CB1 at receptorial level is associated with cirrhotic cardiomiopathy. On the contrary CB2 seems to be a protector against cirrhosis, and this leads to the hypothesis of using certain agonists in treating this pathology
- portal hypertension – CB1 inhibition with SR141716A reduces hematic flux of mesenteric arteria and portal pressure
- hepatic encephalopathy – CB2 agonists (HU308) determine an improvement of cognitive function [1] and demonstrate themselves as having a positive effect on hepatic encephalopathy.
Endocannabinoids are neuromediators involved in neural webs deputized to controlling appetite, pain perception and body temperature regulation. They have also been found in the extra-pyramidal system.
The endocannabinoid system may be defined as a complex of neurotransmissions capable of regulating neuronal excitability.
CB1 distribution is mainly cerebral. The primary regions, in which cannabinoids appear are fundamentally the substantia nigra, globus pallidus, nucleus caudatus, and the putamen.
They have also been founded in the vagus nerve (X) branch comprehending enteric cholinergic neurons and enteric submucosa ganglia cells.
The discovery of endocannabinoids receptors in the brain has linked them to the control of movement, perception, and the alterations of learning and memory processes [25]; they seem to act with opioids in pain modulation [4] [5] [6] [7] [8]. They also regulate emotive states like pleasure and aggression [26] [27].
Correlations with circuitries that regulate vomit have also been found [28].
Furthermore involvements of endocannabinoids exist in the modulation of the spasticity associated with multiple sclerosis [29], while correlations with epilepsy have been underlined: endocannabinoids would act by modulating convulsive activity, with anti-convulsivant properties [30].
This series of consideration helps understand how the central nervous system is more and more considered as the key element in the regulation, prevention, and care of most major metabolic dysfunctions such as diabetes, NAFLD, or metabolic syndrome. It has often been demonstrated how therapies act also at central level and how forms of integrated therapies guarantee better success in treatment, such as in the case of behavior-cognitive psychotherapy, which is able to lead to metabolic re-balance with significant results. [31].
Given the function of CB1 in regulating hunger, the use of its antagonists has been hypothesized against obesity: in fact, it has been shown that rimonabant lead to a reduction in weight, even if associated with the onset of depression and anxiety. Agonists with metabolic effect but no effect on behavior would have the greatest potential [19].
CB1 antagonists such as rimonabant (for two weeks) have determined, in models of cirrhosis, reduction in the formation of ascites and the reduction of hepatic fibrosis [32] in animals (rats); the same molecules are also involved in reducing hepatic damage, while appearing to favor tissue reparation [1].
This helps understand how endocannabinoids are revealing themselves more and more as essential target in the therapy of dysmetabolic pathologies like NAFLD, and of its advanced stage of cirrhosis, not only thanks to the peripheral action of these molecules but also due to their central re-balancing of mechanisms at the base of metabolic dysfunctions.
On the other hand we can hypothesize the use of CB2 agonists in treating hepatic cirrhosis, perhaps they would not be psychoactive: this thanks to findings that demonstrate reduced fibrosis and minor response to damage by CB2 agonist JWH-133 [33].
In light of their correlations with the central nervous system, more and more molecules capable of generating metabolic effects generally on obesity and on organ metabolic dysfunctions like NAFLD can be hypothesized, even if doubts arise in regard to which central functions are specifically controlled. It is certain however that a correct and metabolically-controlled lifestyle (thanks to diet and physical activity) with a more global interpretation of how metabolism is conceived, remains the basis for interaction with other forms of therapy.
1. Tam J, Liu J, Mukhopadhyay B, Cinar R, Godlewski G, Kunos G. (2011) Endocannabinoids in liver disease. Hepatology. 2011 Jan;53(1):346-55. doi: 10.1002/hep.24077.
2. Mallat A, Lotersztajn S (2007) Endocannabinoids and liver disease. Endocannabinoids and their receptors in the liver. American Journal of Physiology. Gastrointestinal and Liver Physiology. 29 october 2007.
3. Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C. (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem. 2002 Feb;80(3):448-56
4. Richardson JD, Aanonsen L, Hargreaves KM. (1998) Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol. 1998 Mar 19;345(2):145-53.
5. Meng ID, Manning BH, Martin WJ, Fields HL. (1998) An analgesia circuit activated by cannabinoids. Nature. 1998 Sep 24;395(6700):381-3.
6. Calignano A, La Rana G, Giuffrida A, Piomelli D. (1998) Control of pain initiation by endogenous cannabinoids. Nature, (1998) 394:277-281.
7. Welch SP, Eads M. (1999) Synergistic interactions of endogenous opioids and cannabinoid systems. Brain Res. 1999 Nov 27;848(1-2):183-90.
8. Cravatt BF, Lichtman AH. (2004) The endogenous cannabinoid system and its role in nociceptive behavior. Neurobiol. 2004 Oct;61(1):149-60.
9. Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G. (1997) Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature, (1997) 390:518-521.
10. Varga K, Wagner JA, Bridgen DT, Kunos G. (1998) Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J, (1998) 12:1035-1044.
11. Randall MD, Kendall DA, O'Sullivan S. (2004) The complexities of the cardiovascular actions of cannabinoids. Br J Pharmacol. 2004 May;142(1):20-6.
12. Bisogno T, Maurelli S, Melck D, De Petrocellis L, Di Marzo V. (1997) Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem, (1997) 272:3315-3323.
13. M. Salzet, C. Breton, T. Bisogno and V. Di Marzo (2000) “Comparative biology of the endocannabinoid system. Possible role in the immune response” ,Eur. J. Biochem.(2000), 267, 4917-4927
14. Croxford JL, Yamamura T. (2005) Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J Neuroimmunol. 2005 Sep;166(1-2):3-18.
15. Bifulco M, Di Marzo V. (2002) Targeting the endocannabinoid system in cancer therapy: a call for further research. Nat Med. 2002 Jun;8(6):547-50.
16. Caraceni P, Domenicali M, Giannone F, Bernardi M. (2009) The role of the endocannabinoid system in liver diseases. Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):65-77.
17. Caraceni P, Viola A, Piscitelli F, Giannone F, Berzigotti A, Cescon M, Domenicali M, Petrosino S, Giampalma E, Riili A, Grazi G, Golfieri R, Zoli M, Bernardi M, Di Marzo V. (2010) Circulating and hepatic endocannabinoids and endocannabinoid-related molecules in patients with cirrhosis. Liver Int. 2010 Jul;30(6):816-25. Epub 2009 Oct 14.
18. Bátkai S, Osei-Hyiaman D, Pan H, El-Assal O, Rajesh M, Mukhopadhyay P, Hong F, Harvey-White J, Jafri A, Haskó G, Huffman JW, Gao B, Kunos G, Pacher P. (2007) Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J. 2007 Jun;21(8):1788-800. Epub 2007 Feb 27.
19. Tam J, Vemuri VK, Liu J, Bátkai S, Mukhopadhyay B, Godlewski G, Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J, Makriyannis A, Kunos G. (2010) Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 2010 Aug 2;120(8):2953-66. doi: 10.1172/JCI42551. Epub 2010 Jul 26.
20. Després JP, Golay A, Sjöström L; Rimonabant in Obesity-Lipids Study Group. (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005 Nov 17;353(20):2121-34.
21. Dvorak M, Watkinson A, McGlone F, Rukwied R. (2003) Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflamm Res. 2003 Jun;52(6):238-45.
22. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G. (2005) Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005 May;115(5):1298-305.
23. Lotersztajn S, Teixeira-Clerc F, Julien B, Deveaux V, Ichigotani Y, Manin S, Tran-Van-Nhieu J, Karsak M, Zimmer A, Mallat A. (2007) CB2 receptors as new therapeutic targets for liver diseases. Br J Pharmacol. 2008 Jan;153(2):286-9. Epub 2007 Oct 22.
24. Domenicali M, Ros J, Fernández-Varo G, Cejudo-Martín P, Crespo M, Morales-Ruiz M, Briones AM, Campistol JM, Arroyo V, Vila E, Rodés J, Jiménez W. (2005) Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors. Gut. 2005 Apr;54(4):522-7.
25. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B. (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002 Aug 1;418(6897):530-4.
26. Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol. 1199;58:315-348.
27. Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998) Endocannabinois: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 1998;21:521-528.
28. Dardani NA (2001) Delta(9)-tetrahydrocannabinol and synthetic cannabinoids prevend emesis produced by the cannabinoid CB1 receptor antagonist-inverse agonist SR141716A. neuropsychopharmacology 2001 Feb;24(2):198-203
29. Baker D (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000;404:84-87
30. Wallace MJ, Martin BR, DeLorenzo RJ. (2002) Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur J Pharmacol. 2002 Oct 11;452(3):295-301.
31. Moscatiello S, Di Luzio R, Bugianesi E, Suppini A, Hickman IJ, Di Domizio S, Dalle Grave R, Marchesini G (2011) Cognitive-behavioral treatment of nonalcoholic Fatty liver disease: a propensity score-adjusted observational study.Obesity (Silver Spring). Apr;19(4):763-70. Epub 2010 Oct 21.
32. Domenicali M, Caraceni P, Giannone F, Pertosa AM, Principe A, Zambruni A, Trevisani F, Croci T, Bernardi M. (2009) Cannabinoid type 1 receptor antagonism delays ascites formation in rats with cirrhosis. Gastroenterology. 2009 Jul;137(1):341-9. Epub 2009 Jan 14.
33. Muñoz-Luque J, Ros J, Fernández-Varo G, Tugues S, Morales-Ruiz M, Alvarez CE, Friedman SL, Arroyo V, Jiménez W. (2008) Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J Pharmacol Exp Ther. 2008 Feb;324(2):475-83. Epub 2007 Nov 20.