Smnd-309 Protective Effect On Acute Liver Injury

The liver is the largest substantial organ in vivo, called a biochemical reactor where a multiplicity of functions play important roles in metabolism, such as biosynthesis of plasma proteins, gluconeogenesis, and detoxification by which toxic compounds can be transformed into less harmful products to reduce toxicity. Hepatic injury is associated with these metabolic dysfunctions. A variety of liver damage caused harmful factors, including alcoholic liver injury, viral liver damage, immune liver injury and other types of drug-induced liver injury. The treatment of liver injury has been the subject of global concern. Therefore, how to effectively prevent various types of liver disease has become widespread international attention. Salvianolic acid B is the major water-souble components in danshen, and has strong biological activity, and played an important role in the treatment of cardiovascular disease, chronic hepatitis, anti-atherosclerosis and improve memory funtion. SMND-309, is a new derivate of salvianolic acid B synthesized by scientists of the Department of Chemistry, Shandong Engineering Research Center for Nature Drug (Chinese patent:CN 20071005108.8). In this study, we investigated the hepatoprotective effects of SMND-309 on animal models of acute liver injury and identify the possible mechanisms underlying hepatoprotective effects of SMND-309.Methods:SMND-309 in saline was administered intraperitoneally (i.p.) at different does once daily for 7 consecutive days. Three h after the final treatment, the mice were treated with CCl4 (20 mg/kg body weight, intraperitoneally (i.p.) dissolved in plant oil (0.1%, v/v)), to establish the model of acute liver injury in mice. Twenty-four h after administration of CCl4, blood was removed to determine serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin (TBIL) activities; liver homogenate malondialdehyde (MDA) content, glutathione (GSH) content, superoxide dismutase (SOD) activity, glutathion peroxidase (GSH-Px) activity, glutathione S-transferase (GST) activity and catalase (CAT) activity. Further, liver histopathology was also determined. In order to explore the possible mechanisms underlying hepatoprotective effects of SMND-309, we determined ATPase, succinate dehydrogenase (SDH) activities, MDA content and GSH content in liver mitochondrial.Result:(1) SMND-309 (15mg/kg) pretreatment significantly decreased the levels of serum ALT, AST, ALP, and TBIL (P<0.05, P<0.01); Liver histopathology also showed that SMND-309 could significantly reduce the incidence of liver lesions induced by CCl4; (2) SMND-309 (15mg/kg) pretreatment significantly increased in SOD, CAT, GSH-Px and GST activities (P<0.05, P<0.01);(3) Pretreatment with SMND-309 significantly decreased CCl4-induced hepatic lipid peroxidation (P<0.01, P<0.05), SMND-309 (5,15mg/kg) also inhabited the increased of MDA content in liver mitochondrial (P<0.05, P<0.01);(4) SMND-309 (15mg/kg) pretreatment significantly improved GSH content both in liver cell and mitochondrial (P<0.05, P<0.01);(5) Pretreatment with SMND-309 significantly increased ATPase in liver mitochondrial and SDH activities also significantly increased when SMND-309 is 15mg/kg (P<0.05).Conclusion:These results suggest that SMND-309 exhibits potent hepatoprotection against CCl4-induced liver damage in mice. The hepatoprotective effects of SMND-309 may due to amelioration of energy metabolism of liver mitochondrial and its antioxidant property.