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 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.

Figures

Fig 1.

TUDCA reduces striatal apoptosis in HD Tg mice. Representative striatal photomicrographs of TUNEL-stained sections are shown for each treatment group. Quantitation of apoptotic cells is indicated in the bar graph. Control Tg HD mice (c) exhibited significantly increased proportions of apoptotic vs. total cells compared with vehicle (a) and TUDCA-treated (b) wt control mice. TUDCA-treated R6/2 mouse striata (d) contained significantly fewer apoptotic cells compared with untreated Tg mice. Sections are counterstained with methyl green. *, P < 0.01 for Tg TUDCA vs. vehicle. (Scale bar, 100 μm.)

Fig 2.

TUDCA significantly reduces cerebral and striatal atrophy in R6/2 HD mice. Representative Nissl-stained striatal sections are shown for each treatment group. The untreated wt striatum (a) is outlined (broken line) for reference and superimposed (solid line) on striata from each of the other groups (b–d). Quantitation of striatal volume and dorsoventral axis measurements are represented graphically. Control R6/2 (c) striatal volume was reduced compared with wt vehicle (a) and TUDCA (b) controls. TUDCA-treated mouse striatal volume (d) was significantly larger than untreated R6/2 mice. Dorsoventral axis measurements were used to quantitate cerebral atrophy. In TUDCA-treated mice, distance of the cerebral dorsoventral axis was significantly larger than Tg controls. *, P < 0.05 for Tg TUDCA vs. vehicle. (Scale bar, 500 μm.)

Fig 3.

TUDCA treatment reduces the size and number of ubiquitinated neuronal intranuclear inclusions (NII) in R6/2 mice. Representative striatal sections are shown for each treatment group, with quantitation of the number and size of striatal NII in bar graphs below. No aggregates were identified in vehicle (a) and TUDCA-treated (b) wt mice. In contrast, vehicle (c) and TUDCA-treated (d) R6/2 mouse striatum contained extensive aggregate formation. Quantitative analysis of TUDCA-treated Tg mice revealed significantly fewer NII compared with R6/2 control animals. Furthermore, NII in TUDCA-treated R6/2 mice were significantly smaller than those in Tg controls (Inset; c and d). hpf, high power field. *, P < 0.05 for Tg TUDCA vs. vehicle. (Scale bar, 100 μm; Inset bar, 20 μm.)

Fig 4.

Quantitation of total squares entered in an open field task as a measurement of R6/2 mouse hypoactivity. Control Tg mice were significantly less active compared with vehicle and TUDCA-treated wt mice. However, TUDCA-treated R6/2 mice were significantly improved compared with vehicle controls. *, P < 0.05 for Tg TUDCA vs. vehicle.

Fig 5.

TUDCA treatment improves Rota-Rod performance in an age- and speed-dependent fashion. Control and TUDCA-treated Tg mice were subjected to the Rota-Rod behavioral task as a measure of sensorimotor ability. Four different speeds with increasing task difficulty were used. Twelve-week-old TUDCA-treated R6/2 mice (white bars) exhibited significant improvement compared with control Tg mice (black bars) at slow (5 rpm) rotational velocity, whereas 11-week-old TUDCA-treated animals performed significantly better at 15 rpm. At 25 rpm, 10- and 11-week-old TUDCA-treated R6/2 mice were markedly better than control Tg animals, whereas at the highest speed (35 rpm), 10-week-old TUDCA-treated mice exhibited significant sensorimotor improvement. *, P < 0.05 for Tg TUDCA vs. vehicle.