Effect of nerve growth factor and role of p38 MAPK signaling pathway in acetaminophen-induced acute liver injury

In this study, the hepatoprotective effect of exogenous nerve growth factor (NGF) and its association with the p38 MAPK signaling pathway were investigated in acetaminophen (APAP)-induced acute liver injury in mice. In the study, 64 male BALB/c mice, 9-10 weeks old, were equally divided into 8 groups as follows; Control, NGF, SB203580, NGF + SB203580, APAP, APAP + NGF, APAP + SB203580 and APAP + NGF + SB203580. All applications (APAP 150 mg/kg, NGF 10 μg/kg and SB203580 20 mg/kg) were made as a single intraperitoneal dose. After 24 hours, the study was terminated by decapitation, and blood and liver tissue samples were taken from the subjects for biochemical (ALT, AST, GGT, GSH, MDA, TAS, TOS), histopathological (Hematoxylin-Eosin staining), immunohistochemical (iNOS, nitrotyrosine, TNF-α, IL-1β, IL-6, IL-10, caspase 3, caspase 8, NGF) and molecular analyses. In the APAP-applied groups, cell damage characterized by hydropic degeneration in hepatocytes in the centrilobular region was determined at different degrees. Cellular damage was found to be more severe in APAP+NGF+SB203580 and APAP+SB203580 groups than in the other groups. Enzymatic damage markers ALT, AST, GGT and oxidative stress-related GSH, MDA, TAS, TOS, iNOS and nitrotyrosine levels did not show significant differences between the groups. It was observed that there was no significant increase in IL-1β and IL-10 levels in APAP group compared to the control group, but the increases in TNF-α and IL-6 expressions were significant. It was determined that TNF-α expression was significantly higher in APAP+NGF+SB203580 group, and IL-1β and IL-6 expressions were also significantly higher in APAP+SB203580 group than in the other groups. It was observed that APAP application increased NGF expression, and the highest expression was observed in APAP+SB203580 group. Caspase 3 and caspase 8 enzyme levels increased in APAP group, and caspase 3 was significantly increased in the APAP+NGF group and caspase 8 was significantly increased in APAP+NGF+SB203580 group. In molecular analysis, p38 mRNA level was found to be higher in APAP group compared to the control group, while no significant difference was found in terms of p38 MAPK expression level between the APAP-applied groups. As a result of our study, it was observed that hepatocytes were able to provide redox homeostasis by buffering the oxidant molecular load at the end of 24 hours. This was thought to be due to the sufficiency of GSH reserves depending on the dose and time relationship and was the most important factor protecting the cells from necrosis in our study. Exogenous NGF administration increased the level of activated caspase 3 through p38 MAPK signaling. Exogenous NGF had no protective effect against APAP hepatotoxicity and inhibition of p38 MAPK signaling caused an increase in damage. It was concluded that further studies evaluating different APAP doses and various stress signals together are needed to reveal the effects of molecular signals and their associations in APAP hepatotoxicity.