Fulminant hepatic failure (FHF) is a life-threatening syndrome characterized by massive hepatic necrosis and high mortality. There is no effective therapy for the disease other than liver transplantation. This study aimed to investigate the effect of agmatine, inducible nitric oxide synthase (iNOS) inhibitor, on D-galactosamine and lipopolysaccharide (GalN/LPS)-induced FHF in mice and explore its possible mechanism(s). Male Swiss albino mice were injected with a single dose agmatine (14 mg/kg, IP) 8 h prior to challenge with a single intraperitoneal injection of both GalN (800 mg/kg) and LPS (50 μg/kg). Agmatine significantly attenuated all GalN/LPS-induced biochemical and pathological changes in liver. It prevented the increase of serum transaminases and alkaline phosphatase (ALP). In addition, agmatine markedly attenuated GalN/LPS-induced necrosis and inflammation. Agmatine significantly reduced oxidative stress and enhanced antioxidant enzymes. Importantly, agmatine decreased total nitric oxide (NO) and pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α). These findings reveal that agmatine has hepatoprotective effects against GalN/LPS-induced FHF in mice that may be related to its ability to suppress oxidative stress, NO synthesis and TNF-α production. Therefore, agmatine may serve as a novel therapeutic strategy for hepatic inflammatory diseases.

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The present study was undertaken to investigate the effect of the new formyl peptide receptor 2/lipoxin A4 receptor agonist BML-111 on acetaminophen (APAP)-induced liver injury in mice and explore its possible mechanism(s). Male Swiss albino mice were intraperitoneally injected with BML-111 (1 mg/kg) twice daily for five consecutive days prior to a single intraperitoneal injection of APAP (500 mg/kg). Results have shown that APAP injection caused liver damage as indicated by significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Liver histopathological examination revealed marked necrosis and inflammation. Additionally, APAP decreased activities of hepatic glutathione (GSH) and superoxide dismutase (SOD) with significant increase in the hepatic malondialdehyde (MDA) content. Furthermore, APAP increased serum nitrite/nitrate (NO(2) (-)/NO(3) (-)) level and hepatic tumor necrosis factor alpha (TNF-α). Pretreatment with BML-111 significantly reversed all APAP-induced pathological changes. BML-111 prevented the increase of AST, ALT, and ALP. Also, BML-111 markedly attenuated APAP-induced necrosis and inflammation. It decreased MDA with increase in SOD and GSH. Importantly, BML-111 decreased NO(2) (-)/NO(3) (-) level and TNF-α. These findings suggest that BML-111 has hepatoprotective effects against APAP-induced liver injury in mice. Its protective effect may be attributed to its ability to counteract the inflammatory ROS generation and regulate cytokine effects.