ursodoxicoltaurine and Huntington-Disease

Huntington's disease (HD) is an untreatable neurological disorder caused by selective and progressive degeneration of the caudate nucleus and putamen of the basal ganglia. Although the etiology of HD pathology is not fully understood, the observed loss of neuronal cells is thought to occur primarily through apoptosis. Furthermore, there is evidence in HD that cell death is mediated through mitochondrial pathways, and mitochondrial deficits are commonly associated with HD. We have previously reported that treatment with tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, prevented neuropathology and associated behavioral deficits in the 3-nitropropionic acid rat model of HD. We therefore examined whether TUDCA would also be neuroprotective in a genetic mouse model of HD. Our results showed that systemically administered TUDCA led to a significant reduction in striatal neuropathology of the R6/2 transgenic HD mouse. Specifically, R6/2 mice began receiving TUDCA at 6 weeks of age and exhibited reduced striatal atrophy, decreased striatal apoptosis, as well as fewer and smaller size ubiquitinated neuronal intranuclear huntingtin inclusions. Moreover, locomotor and sensorimotor deficits were significantly improved in the TUDCA-treated mice. In conclusion, TUDCA is a nontoxic, endogenously produced hydrophilic bile acid that is neuroprotective in a transgenic mouse model of HD and, therefore, may provide a novel and effective treatment in patients with HD.

Topics: Animals; Apoptosis; Bile Acids and Salts; Cell Nucleus; Corpus Striatum; Disease Models, Animal; Huntington Disease; Male; Mice; Mice, Transgenic; Motor Activity; Nerve Degeneration; Neurons; Neuroprotective Agents; Taurochenodeoxycholic Acid

There is currently no effective treatment for Huntington's disease (HD), a progressive, fatal, neurodegenerative disorder characterized by motor and cognitive deterioration. It is well established that HD is associated with perturbation of mitochondrial energy metabolism. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, can stabilize the mitochondrial membrane, inhibit the mitochondrial permeability transition, decrease free radical formation, and derail apoptotic pathways. Here we report that TUDCA significantly reduced 3-nitropropionic acid (3-NP)-mediated striatal neuronal cell death in cell culture. In addition, rats treated with TUDCA exhibited an 80% reduction in apoptosis and in lesion volumes associated with 3-NP administration. Moreover, rats which received a combination of TUDCA + 3-NP exhibited sensorimotor and cognitive task performance that was indistinguishable from that of controls, and this effect persisted at least 6 months. Bile acids have traditionally been used as therapeutic agents for certain liver diseases. This is the first demonstration, however, that a bile acid can be delivered to the brain and function as a neuroprotectant and thus may offer potential therapeutic benefit in the treatment of certain neurodegenerative diseases.

Topics: Animals; Cell Death; Cells, Cultured; Cognition; Corpus Striatum; Disease Models, Animal; Female; Huntington Disease; Mitochondria; Motor Activity; Nerve Degeneration; Neurotoxins; Nitro Compounds; Propionates; Rats; Rats, Inbred F344; Taurochenodeoxycholic Acid

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 determine if and how the taurine-conjugated UDCA, tauroursodeoxycholic acid (TUDCA), inhibits apoptosis induced by 3-NP. Our results indicate that coincubation of cells with TUDCA and 3-NP was associated with an approximately 80% reduction in apoptosis (p < 0.001), whereas neither taurine nor cyclosporin A, a potent inhibitor of the mitochondrial permeability transition (MPT), inhibited cell death. Moreover, TUDCA, as well as UDCA and its glycine-conjugated form, glycoursodeoxycholic acid, prevented mitochondrial release of cytochrome c (p < 0.001), which probably accounts for the observed inhibition of DEVD-specific caspase activity and poly(ADP-ribose) polymerase cleavage. 3-NP decreased mitochondrial transmembrane potential (p < 0.001) and increased mitochondrial-associated Bax protein levels (p < 0.001). Coincubation with TUDCA was associated with significant inhibition of these mitochondrial membrane alterations (p < 0.01). The results suggest that TUDCA inhibits 3-NP-induced apoptosis via direct inhibition of mitochondrial depolarization and outer membrane disruption, together with modulation of Bax translocation from cytosol to mitochondria. In addition, cell death by 3-NP apparently occurs through pathways that are independent of the MPT.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspases; Cells, Cultured; Cytochrome c Group; Hepatocytes; Huntington Disease; Intracellular Membranes; Mitochondria; Mitochondrial Swelling; Neurons; Nitro Compounds; Permeability; Poly(ADP-ribose) Polymerases; Propionates; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid