Tauroursodeoxycholic acid partially prevents apoptosis induced by 3-nitropropionic acid: Evidence for a mitochondrial pathway independent of the permeability transition

Ursodeoxycholic acid (UDCA) has been shown to be a strong modulator of the apoptotic threshold in both hepatic and nonhepatic cells. 3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, appears to cause apoptotic neuronal cell death in the striatum, reminiscent of the neurochemical and anatomical changes associated with Huntington's disease ( HD). This study was undertaken (a) to characterize further the mechanism by which 3-NP induces apoptosis in rat neuronal RN33B cells and (b) to determ ine if and how the taurine-conjugated UDCA, tauroursodeoxycholic acid (TUDC A), inhibits apoptosis induced by 3-NP, Our results indicate that coincubat ion of cells with TUDCA and 3-NP was associated with an similar to 80% redu ction in apoptosis (p < 0.001), whereas neither taurine nor cyclosporin A, a potent inhibitor of the mitochondria[ permeability transition (MPT), inhi bited cell death. Moreover, TUDCA, as well as UDCA and its glycine-conjugat ed form, glycoursodeoxycholic acid, prevented mitochondrial release of cyto chrome c (p < 0.001), which probably accounts for the observed inhibition o f DEVD-specific caspase activity and poly(ADP-ribose) polymerase cleavage. 3-NP decreased mitochondrial transmembrane potential (p < 0.001) and increa sed mitochondrial-associated Bar protein levels (p < 0.001). Coincubation w ith TUDCA was associated with significant inhibition of these mitochondrial membrane alterations (p < 0.001). The results suggest that TUDCA inhibits 3-NP-induced apoptosis via direct inhibition of mitochondrial depolarizatio n and outer membrane disruption, together with modulation of Bar translocat ion from cytosol to mitochondria. In addition, cell death by 3-NP apparentl y occurs through pathways that are independent of the MPT.