title: Rosmarinic acid ameliorates acute liver damage and fibrogenesis in carbon tetrachloride-intoxicated mice.
abstract: The aim of this study was to investigate the therapeutic potential of rosmarinic acid (RA), a natural phenolic, in the treatment of acute liver toxicity. RA at 10, 25 and 50mg/kg was administered by gavage once daily for 2 consecutive days, 6h after CCl(4) intoxication. CCl(4) intoxication caused hepatic necrosis and increased serum ALT activity. In the livers, oxidative/nitrosative stress was evidenced by increased 3-nitrotyrosine (3-NT) and thiobarbituric acid reactive substances (TBARS) formation and a significant decrease in Cu/Zn superoxide dismutase (SOD) activity. CCl(4) administration triggered inflammatory response in mice livers by activating nuclear factor-kappaB (NF-κB), which coincided with the induction of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2). RA improved histological and serum markers of liver damage and significantly ameliorated oxidative/nitrosative stress and inflammatory response in liver tissue. Additionally, RA prevented transforming growth factor-beta1 (TGF-β1) and alpha-smooth muscle actin (α-SMA) expression, suggesting suppression of profibrotic response. Furthermore, RA significantly inhibited the CCl(4)-induced apoptosis, which was evident from decreased cleavage of caspase-3. The hepatoprotective activity of RA coincided with enhanced NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. The results of this study indicates that RA possesses antioxidant, anti-inflammatory, antiapoptotic and antifibrotic activity against acute liver toxicity.
authors.affiliation: Department of Chemistry and Biochemistry, School of Medicine, University of Rijeka, Rijeka, Croatia. robertd@medri.uniri.hr
authors.forename: Robert
authors.initials: R
authors.lastname: Domitrović
authors.forename: Marko
authors.initials: M
authors.lastname: Skoda
authors.forename: Vanja
authors.initials: V
authors.lastname: Vasiljev Marchesi
authors.forename: Olga
authors.initials: O
authors.lastname: Cvijanović
authors.forename: Ester
authors.initials: E
authors.lastname: Pernjak Pugel
authors.forename: Maja Bival
authors.initials: MB
authors.lastname: Stefan
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy* / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D053630:Depsides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D017114:Liver Failure, Acute / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000097123:Rosmarinic Acid
chemical_list: D000410:Alanine Transaminase; D000975:Antioxidants; D002251:Carbon Tetrachloride; D002934:Cinnamates; D051546:Cyclooxygenase 2; D053630:Depsides; D016328:NF-kappa B; D013482:Superoxide Dismutase; D053773:Transforming Growth Factor beta1; D000097123:Rosmarinic Acid; C077623:Ptgs2 protein, mouse