Preventive and therapeutic effects of oleuropein against carbon tetrachloride-induced liver damage in mice.
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 (CCl(4))-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 CCl(4) administration (the preventive treatment), or once daily for 2 consecutive days 6h after CCl(4) intoxication (the curative treatment). CCl(4) 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. CCl(4) 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.
Department of Chemistry and Biochemistry, School of Medicine, University of Rijeka, Rijeka, Croatia. robertd@medri.hr
Robert
R
Domitrović
Hrvoje
H
Jakovac
Vanja Vasiljev
VV
Marchesi
Ivana
I
Šain
Željko
Ž
Romić
Dario
D
Rahelić
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D057888:Iridoid Glucosides; D039823:Iridoids; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D029592:Oleaceae; D018384:Oxidative Stress / Q000187:drug effects; D011714:Pyrans / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D057888:Iridoid Glucosides; D039823:Iridoids; D011714:Pyrans; C002769:oleuropein; D002251:Carbon Tetrachloride; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D005978:Glutathione