Endocannabinoids anandamide and its cannabinoid receptors in liver fibrosis after murine schistosomiasis

Abstract

This study examined endogenous cannabinoid (ECB)-anandamide (AEA) and its cannabinoid receptors (CBR) in mice liver with the development of schistosoma japonicum. Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens. Liver fibrosis was pathologically confirmed nine weeks after the infection. High performance liquid chromatography (HPLC) was employed to determine the concentration of AEA in the plasma of mice. Immunofluorescence was used to detect the expression of CBR1 and CBR2 in liver tissue. Morphological examination showed typical pathological changes, with worm tubercles of schistosoma deposited in the liver tissue, fibrosis around the worm tubercles and infiltration or soakage of inflammatory cells. Also, CBR1 and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups, but they were obviously enhanced in the schistosoma-infected mice. However, the average optical density of CBR1 in the negative control and fibrosis group was 13.28±7.32 and 30.55±7.78, and CBR2 were 28.13±6.42 and 52.29±4.24 (P<0.05). The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group. The concentrations of AEA were (0.37±0.07) and (5.67±1.34) ng/mL (P<0.05). It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice. Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.

Keywords

anandamide / cannabinoid receptor / liver fibrosis / schistosoma japonicum

References

[1] UtzingerJ., ZhouX.N., ChenM.G., et al. . Conquering schistosomiasis in China: the long march. Acta Trop, 2005, 96(2–3): 69-96

[2] ZhouX.N., WangL.Y., ChenM.G., et al. . The public health significance and control of schistosomiasis in China — then and now. Acta Trop, 2005, 96(2–3): 97-105

[3] ManzellaA., OhtomoK., MonzawaS., et al. . Schistosomiasis of the liver. Abdom Imaging, 2008, 33(2): 144-150

[4] JiaT.W., ZhouX.N., WangX.H., et al. . Assessment of the age-specific disability weight of chronic schistosomiasis japonica. Bull World Health Organ, 2007, 85(6): 458-465

[5] ChenH., HeY.W., LiuW.Q., et al. . Rosiglitazone prevents murine hepatic fibrosis induced by Schistosoma japonicum. World J Gastroenterol, 2008, 14(18): 2905-2911

[6] JimenezW.. Endocannabinoids and liver disease. Hepatology, 2005, 41(5): 983-985

[7] MoeziL., GaskariS.A., LeeS.S.. Endocannabinoids and liver disease. V. endocannabinoids as mediators of vascular and cardiac abnormalities in cirrhosis. Am J Physiol Gastrointest Liver Physiol, 2008, 295(4): 649-653

[8] JulienB., GrenardP., Teixeira-ClercF., et al. . Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology, 2005, 128(3): 742-755

[9] Teixeira-ClercF., JulienB., GrenardP., et al. . CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med, 2006, 12(6): 671-676

[10] MaccarroneM., Finazzi-AgroA.. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death Differ, 2003, 10(9): 946-955

[11] SarkerK.P., MaruyamaI.. Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1: possible involvement of lipid rafts. Cell Mol Life Sci, 2003, 60(6): 1200-1208

[12] SiegmundS.V., UchinamiH., OsawaY., et al. . Anandamide induces necrosis in primary hepatic stellate cells. Hepatology, 2005, 41(5): 1085-1095

[13] LiuH.Y., YangQ., DuanR.X., et al. . Effects of anandamide on the activation and proliferation of hepatic stellate cells through cannabinoid-2 receptors. Zhonghua Gan Zang Bing Za Zhi (Chinese), 2008, 16(6): 430-434

[14] MallatA., LoterszatjnS.. Endocananbinoids as novel mediators of liver disease. J Endocrinol Invest, 2006, 29(suppl3): 58-65

[15] BatkaiS., WagnerJ.A., GoparajuS.K., et al. . Endocanabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med, 2001, 7(7): 827-832

[16] SchmidtA., BruneK., HinzB.. Determination of the endocannabinoid anandamide in human plasma by high-performance liquid chromatography. Biomed Chromatogr, 2006, 20(4): 336-342

[17] KogaD., SantaT., HagiwaraK., et al. . High-performance liquid chromatography and fluorometric detection of arachidonylethanolamide (anandamide) and its analogues, derivatized with 4-(N-chloroformylmethyl-N-methyl) amino-7-N, N-dimethylaminosulp honyl-2, 1, 3-benzoxadiazole (DBD-COCl). Biomed Chromatogr, 1995, 9(1): 56-57

[18] Di MarzoV., BifulcoM., PetrocellisL.. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov, 2004, 3(9): 771-784

[19] DevaneW.A., HanusL., BreuerA., et al. . Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 1992, 258(5090): 1946-1949

[20] MechoulamR., PanikashviliD., ShohamiE.. Cannabinoids and brain injury: therapeutic implications. Trends Mol Med, 2002, 8(2): 58-61

[21] MaccarroneM., Finazzi-AgroA.. Endocannabinoids and their actions. Vitam Horm, 2002, 65: 225-255

[22] LynnA.B., HerkenhamM.. Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther, 1994, 268(3): 1612-1623

[23] De FilippisD., D’AmicoA., IuvoneT.. Cannabinomimetic control of mast cell mediator release: new perspective in chronic inflammation. J Neuroendocrinol, 2008, 20(Suppl1): 20-25

[24] PacherP., GaoB.. Endocannabinoids and liver disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases. Am J Physiol Gastrointest Liver Physiol, 2008, 294(4): 850-854

[25] SiegmundS.V., SchwabeR.F.. Endocannabinoids and liver disease. II. Endocannabinoids in the pathogenesis and treatment of liver fibrosis. Am J Physiol Gastrointest Liver Physiol, 2008, 294(2): 357-362

[26] Teixeira-ClercF., JulienB., GrenardP., et al. . The endocannabinoid system as a novel target for the treatment of liver fibrosis. Pathol Biol (Paris), 2008, 56(1): 36-38

[27] Osei-HyiamanD., DePetrilloM., PacherP., et al. . Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest, 2005, 115(5): 1298-1305

[28] BiswasK.K., AbeyamaK., KawaharaK., et al. . Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis. Hepatology, 2003, 38(5): 1167-1177

[29] RosJ., ClariaJ., To-FiguerasJ., et al. . Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat. Gastroenterology, 2002, 122(1): 85-93

[30] LotersztajnS., Teixeira-ClercF., HezodeC., et al. . Endocannabinoids: therapeutic perspectives in chronic liver diseases. Gastroenterol Clin Biol, 2007, 31(3): 255-258

[31] LotersztajnS., Teixeira-ClercF., JulienB., et al. . CB2 receptors as new therapeutic targets for liver diseases. Br J Pharmacol, 2008, 153(2): 286-289

[32] BatkaiS., Osei-HyiamanD., PanH., et al. . Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J, 2007, 21(8): 1788-1800