Targeting sirtuin 1/nuclear factor erythroid 2-related factor 2/tumor necrosis factor-α pathway to modulate hepatic...

Hepatic ischemia reperfusion (HIR) injury is a major complication affecting various major liver surgeries, including liver transplantation. Aprepitant (APRE), a neurokinin-1 receptor antagonist, is commonly used as an antiemetic to prevent chemotherapy-induced nausea and vomiting.

To assess the potential protective effect of APRE against HIR-induced liver injury via targeting the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing receptor 3/interleukin (IL)-1beta signaling pathway.

Six groups of adult male Wistar albino rats were divided as follows: Sham group, Sham/APRE10 group (APRE 10 mg/kg), HIR group, HIR/APRE5 group (APRE 5 mg/kg), HIR/APRE10 group (APRE 10 mg/kg), and HIR/APRE20 group (APRE 20 mg/kg). Serum alanine transaminase, aspartate transaminase, liver malondialdehyde, total antioxidant capacity levels, as well as IL-6, sirtuin 1 (Sirt1), caspase-3, cleaved caspase-3, and tumor necrosis factor alpha biomarkers, were evaluated. Hepatic specimens were examined histopathologically and immunohistochemically for nuclear factor erythroid-2-related factor 2 (Nrf2) immunoexpression.

HIR resulted in hepatic damage, as evidenced by histopathological changes and a significant increase in serum alanine transaminase, aspartate transaminase, hepatic malondialdehyde, caspase-3, and tumor necrosis factor alpha levels. Additionally, there were significant increases in hepatic total antioxidant capacity and reductions in IL-6 and cleaved caspase-3 protein levels, as demonstrated by Western blot analysis, along with enhanced immunoexpression of Sirt1 and Nrf2. APRE has significantly reduced various parameters of oxidative stress, inflammation, and apoptosis, and a significant increase in liver Nrf2 immunoexpression, leading to a significant improvement in the histopathological changes.

In conclusion, targeting the Sirt1/Nrf2 signaling pathway, as demonstrated by APRE in our model, could present a promising therapeutic target to protect against HIR-induced liver injury during major liver surgeries.