5. THE ROLE OF BILE ACIDS IN THE MODULATION OF APOPTOSIS

Bile acids are inherently toxic molecules, which can have a profound influence on cellular function and structure. The proposed mechanisms of bile acid-induced hepatocyte damage range from a simple detergent effect on binding to plasma membranes to the induction of cell death. Bile acids induce apoptosis via ligand-independent, death receptor pathways, involving the Fas receptor and also through classic mitochondrial pathways. In contrast, the oral administration of UDCA and TUDCA has been used clinically for years to treat cholestasis and a number of other liver diseases. There is now strong evidence that the cytoprotective mechanism of UDCA and its conjugates results from their ability to inhibit apoptosis in hepatic cells. Interestingly, the anti-apoptotic properties of these bile acids are independent of the cell type and death signal, suggesting a common anti-apoptotic mechanism(s). Specifically, UDCA prevents apoptosis by modulating mitochondrial membrane perturbation, opening of the permeability transition pore, Bax translocation, cytochrome c release, and subsequent caspase activation and substrate cleavage. In addition, apoptosis can not only be inhibited by blocking pro-apoptotic pathways but also by activating survival signals for example through the cAMP, Akt, NF-κB, MAPK and PI3K-mediated pathways. Bile acids, including UDCA, are potent intracellular signaling molecules with crucial regulatory properties. Thus, by acting as general modulators of cell function, UDCA and TUDCA may play an essential role as therapeutic agents in the treatment of non-liver diseases in which cell survival is compromised, such as in neurodegenerative disorders. Indeed, animal experiments have provided evidence that TUDCA may be effective in ameliorating the HD phenotype in a pharmacological rat model as well as in a transgenic mouse model. The ability of TUDCA to prevent neurologic insult, however, may not be confined only to HD. In fact, treatment of embryonic nigral cells improves graft survival and function in a rat model of Parkinson's disease, while acute neuronal injury associated with ischemic or hemorrhagic stroke may be reduced by administration of TUDCA. As a hydrophilic bile acid, TUDCA is readily water-soluble, can be administered orally or intravenously, and is associated with minimal toxicity, making it a promising drug for potential further clinical application.