Inhibited TLR-4/NF- κB Pathway Mediated by Cannabinoid Receptor 2 Activation Curbs Ongoing Liver Fibrosis in Bile Duct Ligated Rats

The endocannabinoid system is participated in the pathogenesis of liver fibrosis. Activation of cannabinoid receptor type 2 (CB2) plays a principle role in liver regeneration and protection against liver injury. This study aimed to explore the role of CB2 agonist (AM1241) on suppressing the progress of liver fibrosis induced by bile duct ligation (BDL). AM1241 was administrated to BDL rats in two doses (3 and 6 mg/kg). Liver function and oxidative stress markers, hepatic TNF-α, IL-6 and IL-10, RT-qPCR expression of TLR4 gene, immunohistochemical expression of CD31, CD34, α-SMA and NF-κB as well as histopathology of liver tissue were all assessed. BDL rats (n=9) showed; significant (P<0.05) increase in aminotransferases activity, bilirubin levels, hepatic MDA, TNF-α and IL-6 levels and TLR4 gene-expression with significant decrease in GSH content and IL-10, marked histological fibrosis, pseudolobulation and cholangiolar proliferation with increased immune-expression of CD31, α-SMA and NF-κB with nil expression of CD34. Conversely, AM1241 administration at both doses significantly (P<0.05) ameliorated liver function markers, MDA level, pro-inflammatory cytokines TNF-α and IL-6 and TLR4 gene expression. Additionally, AM1241 significantly (P<0.05) increased GSH content and immunomodulatory cytokine; IL-10. Histologically, AM1241 limited fibroplasia extension, decreased cholongiocytes proliferation, and decreased immune-expression of CD31, α-SMA and NF-κB with strongly expressed CD34. The current study depicts that; CB2 receptors activation promotes liver regeneration and suppresses the progress of liver fibrosis through featured mechanisms including; TLR4/NF-κB pathway-dependent inhibition, suppressing pro-inflammatory cytokines; IL-6 and TNF-α, reducing angiogenesis and stimulating hepatic oval/progenitor cells.