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Papers In Press, published online ahead of print June 16, 2004
Department of Biomedical Sciences, University of Padova, Padova I-35121
Corresponding Author: bernardi{at}bio.unipd.it
We studied the effects of cyclosporin A (CsA) administration (i) on the properties of the permeability transition pore (PTP) in mitochondria isolated from the liver; and (ii) on the susceptibility to hepatotoxicity induced by lipopolysaccharide of E. Coli (LPS) plus D-Galactosamine (D-GalN) in rats. CsA exerted a marked PTP inhibition ex vivo, with an effect that peaked between 2 and 9 h of drug treatment and decayed with an apparent half-time of about 13 h. Administration of LPS plus D-GalN to naïve rats caused the expected increased serum levels of tumor necrosis factor (TNF)-alpha, liver inflammation with BID cleavage, activation of caspase 3, appearance of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei and release of alanine aminotransferase and aspartate aminotransferase into the bloodstream. Treatment with CsA prior to, or within 5 h of the administration of LPS plus D-GalN protected rats from hepatotoxicity despite the normal increase of serum TNF-alpha and BID cleavage. These results indicate that CsA prevents the hepatotoxic effects of TNF-alpha by blocking the mitochondrial proapoptotic pathway through inhibition of the PTP, and provide a viable strategy for the treatment of liver diseases that depend on increased production and/or liver sensitization to TNF-alpha.
J. Biol. Chem, 10.1074/jbc.M405297200
Submitted on May 12, 2004
Revised on June 21, 2004
Accepted on June 16, 2004
Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by TNF-
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