hemopressin and Cholestasis

Curcumin exerts hepatoprotective effects via poorly defined mechanisms. Recently, some studies suggested that this effect was mediated by antagonizing CB1 receptors in hepatic stellate cells. The current study aimed to investigate whether CB1 antagonist, hemopressin, could potentiate the hepatoprotective effect of curcumin, in comparison with silymarin in bile duct-ligated (BDL) rats. Curcumin and hemopressin each alone and in combination ameliorated biochemical and structural fibrotic injury, and downregulated cyclooxygenase-2 (COX-2) and both mRNA and protein levels of nuclear factor kappa B (NF-κB) in fibrotic liver. In contrast to the previous studies, curcumin alone did not affect the gene expression of cannabinoid receptors. However, the combination of hemopressin and curcumin reduced the expression of CB1 in fibrotic liver. Surprisingly, silymarin upregulated CB2 receptors and downregulated CB1 at mRNA level more than all the administered drugs. Both curcumin and hemopressin each alone decreased lipid peroxidation product, malondialdehyde (MDA), while the combination increased the reduced glutathione content. All the administered drugs increased the hepatic antiapoptotic marker, Bcl2. Our study suggests that hemopressin potentiates the hepatoprotective effect of curcumin on fibrotic liver. We identified a new mechanism of the hepatoprotective effect of silymarin via modulation of cannabinoid receptors in fibrotic liver.

Topics: Animals; Cholestasis; Curcumin; Cyclooxygenase 2; Drug Synergism; Glutathione; Hemoglobins; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; NF-kappa B; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; RNA, Messenger; Silymarin

This study assessed the effect of stimulation of CB2 receptors or CB1 blockade on fibrosis and apoptosis in rats subjected to bile duct ligation (BDL). It was performed in sham and BDL rats for four weeks. Fibrosis-induced rats received a CB2 receptor agonist β-caryophyllene, CB1 receptor antagonist, hemopressin, combination of β-caryophyllene and CB2 antagonist, AM630 or vehicle daily during the last 2 weeks of the BDL ligation. Transaminases activity, bilirubin levels, hepatic collagen content, hydroxyproline level, Bcl2 positive hepatocytes, and mRNA expression of CB1, CB2 receptors and matrix metalloproteinase-1 (MMP-1) genes were measured in all animals. Bile duct ligated rats showed increased bilirubin levels, elevated transaminases activity, increased hepatic collagen content, and hydroxyproline level, reduced Bcl2 positive hepatocytes and increased expression of the assessed messengers in comparison with sham rats. However, fibrotic rats treated with either β-caryophyllene or hemopressin had reduced hepatic collagen content, improved transaminase activity and reduced bilirubin level, ameliorated CB1 gene expression, and increased MMP-1 gene expression compared with untreated fibrotic rats. These results were associated with attenuated apoptosis with only β-caryophyllene administration. CB2 receptor blockade by AM630 prevents the effects of β-caryophyllene on CB1 receptor and MMP-1 genes expression. This study points out that either stimulation of CB2 receptors or CB1 blockade can attenuate hepatic fibrosis in bile duct ligated rats. The mechanisms underlying these incidents may open new avenues for attenuating fibrosis and apoptosis of cholestasis- induced liver diseases.

Topics: Animals; Apoptosis; Bile Ducts; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cholestasis; Collagen; Hemoglobins; Hydroxyproline; Indoles; Liver Cirrhosis, Experimental; Male; Matrix Metalloproteinase 1; Peptide Fragments; Polycyclic Sesquiterpenes; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; RNA, Messenger; Sesquiterpenes