Protective effects of antioxidant raxofelast in alcohol-induced liver disease in mice.
We investigated the effect of raxofelast on lipid peroxidation inhibition in mice exposed to chronic ethanol. Female C57BL/6 mice were fed a modified Lieber-DeCarli liquid ethanol (ETOH) or control diet (sham ETOH) for up to 14 days. Animals were assigned to receive either raxofelast (20 mg/kg/day i.p.) or its vehicle (DMSO:NaCl 0.9% 1:1, v:v; 1 ml/kg i.p.). Serum alanine aminotransferase (ALT), plasma and liver triglyceride levels, hepatic malondialdehyde (MDA), reduced glutathione (GSH) concentrations, liver gene expression of Toll-like receptor-4 (TLR-4), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) were studied at the end of the study. A histological evaluation of liver damage was also carried out. Raxofelast, an analog of vitamin E, blunted the increased hepatic nuclear factor-kappaB activity, reduced serum ALT, plasma and liver triglycerides, lowered hepatic MDA levels, prevented liver GSH depletion and decreased TLR-4, TNF-alpha, IL-6 and ICAM-1 hepatic gene expression. Furthermore raxofelast ameliorated liver damage. Our results suggest that raxofelast blunts the inflammatory cascade and organ damage during chronic ethanol exposure.
Altavilla
Domenica
D
Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, AOU G. Martino Messina, Italy.
Marini
Herbert
H
Seminara
Paolo
P
Squadrito
Giovanni
G
Minutoli
Letteria
L
Passaniti
Maria
M
Bitto
Alessandra
A
Calapai
Gioacchino
G
Calò
Margherita
M
Caputi
Achille P
AP
Squadrito
Francesco
F
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000517:prevention & control*; D008111:Liver Function Tests; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D001572:Benzofurans; D015850:Interleukin-6; D016328:NF-kappa B; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D014810:Vitamin E; D008315:Malondialdehyde; D000410:Alanine Transaminase; D005978:Glutathione; C071049:Raxofelast