Protective effects of gastrin-releasing peptide receptor antagonist RC-3095 in an animal model of hepatic ischemia/reperfusion injury.

AIM: We aims to evaluate effects of RC-3095 on mice with hepatic ischemia followed by reperfusion (I/R) injury and further explore the possible underlying mechanism.

METHODS: Mice were subjected to partial hepatic ischemia for 60 min followed by different durations of reperfusion. Levels of gastrin releasing peptide (GRP) and GRP receptor (GRPR) in the blood and liver were detected by ELISA or Western blotting (WB) after 3, 6, 12 or 24 h of reperfusion. RC-3095 or normal saline (control) was administered intraperitoneally at the time of reperfusion. Expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10 in blood and liver samples were examined with ELISA. Neutrophil influx into the liver was assessed by flow cytometry and myeloperoxidase assay. Hematoxylin-eosin (HE) staining of the liver and TUNEL assay were used to determine hepatic injury and hepatocellular necrosis. Activation of nuclear factor (NF)-κB and p38/extracellular regulated protein kinase (ERK) mitogen activated protein kinase (MAPK) was investigated with WB.

RESULTS: The expression of GRP was upregulated within 3 hours after reperfusion and remained elevated for up to 24 h in the liver while GRPR was also upregulated after 3 or 6 hours of reperfusion, but returned to baseline levels within 24 h. RC-3095 significantly reduced the inflammatory hepatic injury, liver neutrophil accumulation and hepatocellular apoptosis, probably via inhibiting activation of NF-κB or p38/ERK MAPK.

CONCLUSION: These findings supported that GRP-GRPR played an important role in hepatic I/R injury, and RC-3095 ameliorated liver damage by suppressing the inflammatory response and hepatocellular necrosis.