Naltrexone protects against BDL-induced cirrhosis in Wistar rats by attenuating thrombospondin-1 and enhancing antioxidant defense system via Nrf-2.

AIMS

It is well-established that thrombospondin-1 (THBS-1), vascular endothelial growth factor-A (VEGF-A), nuclear factor-erythroid 2-related factor 2 (Nrf-2), Kelch-like ECH-associated protein 1 (Keap-1), and transforming growth factor-beta 1 (TGF-β1) are the pivotal players of liver fibrosis. Recent studies have shown that endogenous opioid levels increase during liver cirrhosis. Therefore, the present study aimed to clarify the effect of naltrexone (NTX), an opioid antagonist, on the alteration of these factors following bile duct ligation (BDL)-induced liver cirrhosis.

MAIN METHODS

Wistar male rats (n = 50) were categorized equally into 5 groups (baseline, sham+saline, BDL + saline, sham+NTX (10 mg/kg of body weight (BW)), and BDL + NTX (10 mg/kg of BW)). At the end of the experiment, H&E staining was used to assess necrosis and lobular damage of hepatic tissue. The gene expression of THBS-1 and NADPH oxidase 1 (NOX-1) was measured by real time-PCR and VEGF-A, Nrf-2, Keap-1, and TGF-β1 protein levels were assessed by western blot. The antioxidant enzymes activity, total oxidant status (TOS) and MDA level were measured by commercial kits.

KEY FINDINGS

Hepatic necrosis and lobular damage increased substantially and NTX reduced them markedly in the BDL group. Gene expression of hepatic THBS-1 and NOX-1, TOS and MDA levels increased markedly in the BDL + saline group, and Nrf-2 and VEGF-A values decreased significantly in the BDL + NTX group. NTX recovered THBS-1, NOX-1 and Nrf-2 in the BDL + NTX group, substantially (p-value ≤ 0.05).

SIGNIFICANCE

Data showed that NTX treatment attenuates liver fibrosis mainly by lowering THBS-1 and NOX-1 and increasing Nrf-2 protein level and antioxidant enzymes.