The Protective Effect of Cordycepin on D-Galactosamine/Lipopolysaccharide-Induced Acute Liver Injury.

Jin Li,Liping Zhong,Fengzhong Wang,Haibo Zhu

doi:10.1155/2017/3946706

Abstract

As the major active ingredient of Cordyceps militaris, cordycepin (3′-deoxyadenosine) has been well documented to alleviate inflammation and oxidative stress both in vitro and in vivo. To explore the potential protective effect of cordycepin in fulminant hepatic failure, mice were pretreated with cordycepin for 3 weeks followed by D-galactosamine (GalN)/lipopolysaccharide (LPS) injection. Then we found cordycepin (200 mg/kg) administration elevated survival rate, improved liver function, and suppressed hepatocyte apoptosis and necrosis in mice with severe hepatic damage by GalN/LPS treatment. Further, cordycepin inhibited hepatic neutrophil and macrophage infiltration and prevented proinflammatory cytokine production possibly through suppressing TLR4 and NF-κB signaling transduction. The blockade of reactive oxygen species (ROS) and lipid peroxidation production by cordycepin was associated with the decrease of NAD(P)H oxidase (NOX) activity. Besides, cordycepin significantly prevented excessive autophagy induced by GalN/LPS in the liver. These data suggested that cordycepin could be a promising therapeutic agent for GalN/LPS-induced hepatotoxicity.

Highlights

Fulminant hepatic failure is an unusual but dreaded disease with high mortality, characterized by hepatic dysfunction, coagulation disorder, and later multiple organ failure
LPS is considered as the primary inducer to liver injury, while GalN deteriorates the extent of hepatocyte necrosis by inhibiting RNA and protein synthesis [1]
Compared with mice only treated with GalN/LPS, there was no markedly protective effect in mice administrated with 50 mg/kg cordycepin, but with a dose of 200 mg/kg cordycepin, the survival time significantly prolonged and the mortality markedly decreased approximately by 30% (Figure 1(a))

Summary

Introduction

Fulminant hepatic failure is an unusual but dreaded disease with high mortality, characterized by hepatic dysfunction, coagulation disorder, and later multiple organ failure. D-galactosamine (GalN) and lipopolysaccharide- (LPS-) induced acute liver injury is one of the most commonly used murine model resembling hepatitis virus invasion. LPS is considered as the primary inducer to liver injury, while GalN deteriorates the extent of hepatocyte necrosis by inhibiting RNA and protein synthesis [1]. Recent pharmacological researches demonstrated that LPS treatment combined with GalN promotes proinflammatory cytokine generation in hepatic macrophages, including interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α), which triggers caspase cascade and bring death to hepatocytes [2]. Activated caspase-8 truncates BH3-only BID protein and causes cytochrome c released from mitochondria, cleaving and activating caspase-9. Both caspase-8 and caspase-9 contribute to caspase-3 activation and result in cell apoptosis [3]. Activated macrophages and neutrophils produce massive reactive oxygen species (ROS) through NAD(P)H oxidase (NOX), which accelerates hepatocyte necrosis in further [4]

Methods

Results

Discussion

Conclusion