Preventive and therapeutic effects of oleuropein against carbon tetrachloride-induced liver damage in mice

• Published in: Pharmacological research 2012-04, Vol.65 (4), p.451-464
• Main Authors: Domitrović, Robert, Jakovac, Hrvoje, Marchesi, Vanja Vasiljev, Šain, Ivana, Romić, Željko, Rahelić, Dario
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - therapeutic use; Apoptosis; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Disease Models, Animal; Glutathione - metabolism; Heme Oxygenase-1 - metabolism; Hepatotoxicity; Inflammation; Iridoids; Liver fibrosis; Male; Mice; Mice, Inbred BALB C; Oleaceae; Oleuropein; Oxidative stress; Oxidative Stress - drug effects; Pyrans - therapeutic use; Superoxide Dismutase - metabolism
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2011.12.005

Olives and olive products, an inevitable part of the Mediterranean diet, possess various beneficial effects, such as a decreased risk of cardiovascular disease and cancer. Oleuropein is a non-toxic secoiridoid found in the leaves and fruits of olive (Olea europaea L.). In this study, we have investigated the hepatoprotective activity of oleuropein in carbon tetrachloride (CCl4)-induced liver injury in male BALB/cN mice. Oleuropein in doses of 100 and 200mg/kg was administered intraperitoneally (ip) once daily for 3 consecutive days, prior to CCl4 administration (the preventive treatment), or once daily for 2 consecutive days 6h after CCl4 intoxication (the curative treatment). CCl4 intoxication resulted in a massive hepatic necrosis and increased plasma transaminases. Liver injury was associated with oxidative/nitrosative stress evidenced by increased nitrotyrosine formation as well as a significant decrease in superoxide dismutase activity and glutathione levels. CCl4 administration triggered inflammatory response in mice livers by inducing expression of nuclear factor-kappaB, which coincided with the induction of tumor necrosis factor-alpha, cyclooxygenase-2 and inducible nitric oxide synthase. In both treatment protocols, oleuropein significantly attenuated oxidative/nitrosative stress and inflammatory response and improved histological and plasma markers of liver damage. Additionally, in the curative regimen, oleuropein prevented tumor necrosis factor-beta1-mediated activation of hepatic stellate cells, as well as the activation of caspase-3. The hepatoprotective activity of oleuropein was, at least in part, achieved through the NF-E2-related factor 2-mediated induction of heme oxygenase-1. The present study demonstrates antioxidant, anti-inflammatory, antiapoptotic, and antifibrotic activity of oleuropein, with more pronounced therapeutic than prophylactic effects.