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

Abstract
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.
AuthorsRobert Domitrović, Hrvoje Jakovac, Vanja Vasiljev Marchesi, Ivana Šain, Željko Romić, Dario Rahelić
JournalPharmacological research (Pharmacol Res) Vol. 65 Issue 4 Pg. 451-64 (Apr 2012) ISSN: 1096-1186 [Electronic] England
PMID22214867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Antioxidants
  • Iridoids
  • Pyrans
  • oleuropein
  • Carbon Tetrachloride
  • Heme Oxygenase-1
  • Superoxide Dismutase
  • Glutathione
Topics
  • Animals
  • Antioxidants (therapeutic use)
  • Carbon Tetrachloride
  • Disease Models, Animal
  • Drug-Induced Liver Injury (drug therapy, metabolism, pathology)
  • Glutathione (metabolism)
  • Heme Oxygenase-1 (metabolism)
  • Iridoids
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Oleaceae
  • Oxidative Stress (drug effects)
  • Pyrans (therapeutic use)
  • Superoxide Dismutase (metabolism)

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