Alpha-lipoic acid protects mice against concanavalin A-induced hepatitis by modulating cytokine secretion and reducing reactive oxygen species generation
Introduction
Hepatitis is a severe disease that threatens human health and daily life. It can be caused by a variety of factors including alcohol, viral infections, drugs, poisons, or autoimmune disorders [1], [2], [3]. Concanavalin A (Con A)-induced hepatitis is a well-established mouse model of immune-mediated liver injury. Knowing that its pathological changes are similar to those of human hepatitis in many aspects [4], it has been used as an appropriate model for studying hepatitis. Activated T lymphocyte infiltration, apoptosis and necrosis of hepatocytes are regarded as the prominent character in autoimmune hepatitis [5], [6], [7]. Besides, reactive oxygen species (ROS), a highly reactive and diffusible free radical, is another major mediator of inflammation. Ample evidence indicates that reduction in ROS can attenuate hepatic injury [8], and antioxidant enzymes including superoxide dismutase (SOD) and glutathione (GSH) are shown to play important roles in human hepatitis [9], [10]. ROS can trigger various signaling pathways and redox-sensitive signal transduction that modulates cellular mechanisms for cell proliferation, survival, death, and immune responses by inducing the production of inflammatory factors such as TNF-α, IL-6, IFN-γ and IL-10 through activation of NF-κB [11], [12], [13]. ROS accumulation inhibits mitogen-activated protein kinase (MAPK) phosphatases, resulting in c-Jun N-terminal kinase (JNK) activation, which contributes to ROS accumulation and hepatocyte death [14].
Alpha-lipoic acid (α-LA), also known as thioctic acid (TA) and 1,2 dithiolane-3-pentanoic acid, is a naturally occurring substance existing in almost all types of prokaryotic and eukaryotic cells. It is a key regulator of energy metabolism in mitochondria [15], [16], [17], [18]. The physiologic function of α-LA has been most highlighted as a co-factor of the pyruvate dehydrogenase complex [19]. It is a potent natural antioxidant medium capable of scavenging ROS, chelating metal ions, and regenerating endogenous and exogenous antioxidants [20], [21], [22]. In addition to its well-described antioxidant activities, a-LA also exhibits a distinct regulatory effect on signal transduction processes, playing a central role in tissue damage and protection.
The protective effect of α-LA in the liver has been reported in various liver injuries such as ischemia–reperfusion injury, alcohol-induced damage, metal intoxication, and hyperdynamic circulation in biliary cirrhosis [23], [24], [25], where α-LA suppressed apoptotic and inflammatory pathways, and restored water channels and sodium transporters, suggesting that α-LA might be a candidate for the treatment of Con A-induced autoimmune hepatitis.
The aim of the present study was to see whether administration of α-LA could protect Con A-induced hepatitis in a mouse model and explore the underlying mechanism.
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Materials
α-LA (T5625-500 mg) and Con A (C2272-2 mg) were obtained from Sigma Chemical Company (USA). All the other chemicals and reagents were of standard commercially available biochemical quality.
Model establishment and experimental design
C57BL/6 male mice (aged 6–8 weeks; 20–25 g) were obtained from the Animal Experimentation Center of the Second Military Medical University (Shanghai, China). All animals were acclimatized under controlled temperature (20 °C), humidity (60%) and 12 h light/12 h dark cycle for 1 week before initiation of the
α-LA pretreatment ameliorates Con A-induced hepatitis
First, we examined whether α-LA had a protective effect on Con A-induced hepatitis. Compared with normal control group, serum ALT and AST levels were increased significantly in Con A-treated mice, and α-LA pretreatment significantly attenuated the Con A-induced elevation of ALT and AST (P < 0.01) (Fig. 1A and 1B), suggesting that α-LA had a protective effect against Con A-induced hepatitis. Next, we injected single dose α-LA (100 mg/kg) one hour after the injection of Con A to mice to examine the
Discussion
Liver disease generally refers to a series of common and detrimental diseases including acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC) and autoimmune hepatitis [32]. Acute autoimmune hepatitis, as one of them, seriously threatens human health and daily life. As there is no effective drug currently available for the treatment of hepatitis, it is an urgent task to explore new therapies for clinical practice [33]. In this study, we demonstrated the protective
Acknowledgements
This work was financially supported by grants from the National Nature Science Foundation of China (81471845, 81272065, 81171788, 81201492), Shanghai Scientific and Technological Commission Foundation (12JC1410700).
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Miaomiao Fei, Qun Xie and Yun Zou contributed equally to this work.