Bilirubin and Amyloid-β Peptide Induce Cytochrome c Release Through Mitochondrial Membrane Permeabilization

摘要: BACKGROUND: The pathogenesis of bilirubin encephalopathy and Alzheimer's disease appears to result from accumulation unconjugated (UCB) amyloid-beta (Abeta) peptide, respectively, which may cause apoptosis. Permeabilization the mitochondrial membrane, with release intermembrane proteins, has been strongly implicated in cell death. Inhibition permeability is one pathway by ursodeoxycholate (UDC) tauroursodeoxycholate (TUDC) protect against apoptosis hepatic nonhepatic cells. In this study, we further characterize UCB- Abeta-induced cytotoxicty isolated neural cells, investigate membrane perturbation during incubation mitochondria both agents. addition, evaluate whether anti-apoptotic drugs UDC TUDC prevent any changes occurring. MATERIALS AND METHODS: Primary rat neuron astrocyte cultures were incubated UCB or Abeta either alone presence UDC. Apoptosis was assessed DNA fragmentation nuclear morphological changes. Isolated treated each toxic, combination UDC, TUDC, cyclosporine A. Mitochondrial swelling measured spectrophotometrically cytochrome c protein levels determined Western blot. RESULTS: Incubation cells induced (p 50% < 0.05). Both toxins caused permeabilization 0.001); whereas, pretreatment protective even more effective at preventing matrix mediated 0.01). markedly reduced associated Abeta, respectively Moreover, A significantly inhibited efflux CONCLUSION: peptide activate apoptotic machinery Toxicity occurs through a mitochondrial-dependent pathway, part involves opening transition pore. Furthermore, required for can be prevented TUDC. These data suggest that pharmacological target cytoprotection hyperbilirubinemia neurodegenerative disorders, potential therapeutic