Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease

Abstract

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 R6͞2 transgenic HD mouse. Specifically, R6͞2 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.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Furthermore, TUDCA decreased cerebral atrophy, increased striatal volume and significantly reduced the number and size of striatal NIIs. At the behavioral level, TUDCA administration was shown to increase the activity in the open-field of 10 week-old R6/2 mice as well as the general rotarod performance of 10-12 week-old animals (Keene et al, 2002). However, it is difficult to discern the actual robustness of the effect of TUDCA on this behavioral parameter.…”

“…The administration of tauroursodeoxycholic acid (TUDCA), a bile acid with antioxidant and antiapoptotic properties, starting at an early symptomatic stage (6 weeks of age) was also shown to have beneficial effects in R6/2 mice (Keene et al, 2002). Surprisingly, in contrast to the studies reporting virtually no striatal cell death until a very late stage of the R6/2 phenotype (Iannicola et al, 2000;Turmaine et al, 2000;Yu et al, 2003), these authors were able to observe a marked increase in the number of apoptotic cells [TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)-positive cells] in the striatum of R6/2 mice at 13 weeks of age, a striking finding that was virtually abolished by TUDCA.…”

“…To date, only one study reported a 25% decrease in the total number of striatal cells in 12-week-old transgenic mice (Stack et al, 2005), while another described a marked increase in the number of apoptotic cells in the striatum (Keene et al, 2002) of 13 week-old R6/2 mice. On the other hand, "dark cell degeneration" has also been described in a small number of neurons in 12- (Stack et al, 2005) and 14-week-old mice (i.e., at a very late stage in the development of the disease) (Iannicola et al, 2000;Turmaine et al, 2000;Yu et al, 2003).…”

Genesis of ER stress in Huntington’s Disease

“…As a general strategy for reducing ER stress, there are reports that chemical chaperones, including 4-PBA and TUDCA, hindered disease progression in HD mouse models, and decreased ER stress levels in HD and other disease models [185][186][187]. Reduction of eIF2α-P [159], or treatment with a compound that restores translation downstream of eIF2α, thwarted prion-related disease in mouse models [162].…”

Game and Players: Mitochondrial Apoptosis and the Therapeutic Potential of Ursodeoxycholic Acid

“…In this regard, it has been demonstrated both in vitro and in vivo that tauroursodeoxycholic acid (TUDCA) can benefit certain acute and chronic neurodegenerative disorders, which are associated with increase levels of apoptosis. TUDCA is a potent neuroprotective agent not only in pharmacologic and transgenic animal models of Huntington's disease (Keene et al, 2002;Keene et al, 2001), but also for acute ischemic and hemorrhagic stroke Rodrigues et al, 2002). Considering its clinical safety, UDCA and/or its conjugate derivates may potentially be powerful therapeutic agents in several human apoptosisassociated injuries.…”