Desensitization of the Permeability Transition Pore by Cyclosporin A Prevents Activation of the Mitochondrial Apoptotic Pathway and Liver Damage by TNF-a

We studied the effects of cyclosporin A (CsA) administration 1) on the properties of the permeability transition pore (PTP) in mitochondria isolated from the liver and 2) on the susceptibility to hepatotoxicity induced by lipopolysaccharide of Escherichia 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 DGalN to naive 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-positive nuclei, and release of alanine aminotransferase and aspartate aminotransferase into the bloodstream. Treatment with CsA before 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 provides a viable strategy for the treatment of liver diseases that depend on increased production and/or liver sensitization to TNF-alpha.