Tetrabenazine is neuroprotective in Huntington's disease mice
© Wang et al; licensee BioMed Central Ltd. 2010
Received: 31 December 2009
Accepted: 26 April 2010
Published: 26 April 2010
Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in Huntingtin protein (Htt). PolyQ expansion in Httexp causes selective degeneration of striatal medium spiny neurons (MSN) in HD patients. A number of previous studies suggested that dopamine signaling plays an important role in HD pathogenesis. A specific inhibitor of vesicular monoamine transporter (VMAT2) tetrabenazine (TBZ) has been recently approved by Food and Drug Administration for treatment of HD patients in the USA. TBZ acts by reducing dopaminergic input to the striatum.
In previous studies we demonstrated that long-term feeding with TBZ (combined with L-Dopa) alleviated the motor deficits and reduced the striatal neuronal loss in the yeast artificial chromosome transgenic mouse model of HD (YAC128 mice). To further investigate a potential beneficial effects of TBZ for HD treatment, we here repeated TBZ evaluation in YAC128 mice starting TBZ treatment at 2 months of age ("early" TBZ group) and at 6 months of age ("late" TBZ group). In agreement with our previous studies, we found that both "early" and "late" TBZ treatments alleviated motor deficits and reduced striatal cell loss in YAC128 mice. In addition, we have been able to recapitulate and quantify depression-like symptoms in TBZ-treated mice, reminiscent of common side effects observed in HD patients taking TBZ.
Our results further support therapeutic value of TBZ for treatment of HD but also highlight the need to develop more specific dopamine antagonists which are less prone to side-effects.
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder characterized by chorea, gradual but inexorable cognitive decline, and psychiatric disturbances [1, 2]. Selective and progressive neuronal loss of the striatal medium spiny neurons (MSN) is the major feature of neuropathological changes in HD . The cause of HD is an expanded polyglutamine (polyQ) in the amino-terminus of Huntingtin (Htt), a 350 kDa ubiquitously expressed cytoplasmic protein of unknown function . The cellular mechanisms underlying the cause of MSN neurodegeneration in HD are not very clear, although most experimental evidences indicate that polyQ expansion in Httexp leads to a "toxic gain of function" . A number of toxic functions have been assigned to Httexp, such as effects on gene transcription, formation of toxic aggregates, direct induction of apoptosis, disruption of key neuronal functions such as proteosomal or mitochondrial functions, ubiquitination pathways, axonal transport, endocytosis, synaptic transmission and calcium signaling [4–11].
In addition to glutamatergic stimulation from the cortex, the striatum is the predominant target of dopaminergic neurons that originate from the substantia nigra . There is increasing evidence that the dopaminergic system may contribute to HD neuropathology . Significant reduction of striatal D1 and D2 receptor density has been reported in HD patients [13–18] and HD mouse models [19–22]. High concentration of dopamine may exert direct toxic effects on striatal neurons [23–28]. Hyperdopaminergic transmission has been shown to accelerate the formation of Httexp aggregates and promote motor dysfunction in 92Q knock-in HD mouse model . Recent evidences from our group and from other groups suggested that in HD dopaminergic and glutamatergic signaling pathways act synergistically to enhance the sensitivity of striatal neurons to mutant huntingtin toxicity via disturbed calcium homeostasis  and disregulated Cdk5 signaling . All these studies pointed to an important role of dopaminergic pathway in HD and suggested that dopamine signaling pathway constitute a potential therapeutic target for HD treatment.
Tetrabenazine (TBZ) is a potent blocker of vesicular monoamine transporter (VMAT2). In multiple clinical trials TBZ has been shown to significantly reduce chorea symptoms in HD patients when compared with placebo group [32–35]. In our previous experiments with YAC128 mouse model of HD we demonstarted that long term administration of TBZ (in combination with L-dopa) alleviated motor deficits and reduced striatal cell loss in these mice . In 2008 TBZ became the first drug officially approved by the Food and Drug administration for treatment of HD patients in the United States . In clinical setting most HD patients would receive TBZ at the symptomatic stage after onset of the symptoms. To mimic clinical situation more precisely, we now repeated evaluation of TBZ in YAC128 HD mouse model and compared results obtained in the "early" treatment group (starting TBZ at 2 months, prior to onset of symptoms in YAC128 mice) and "late" treatment group (starting TBZ at 6 months, when motor symptoms start to develop in YAC128 mice). Our results demonstrated significant beneficial effects of TBZ in both "early" and "late" treatment groups of YAC128 HD mice.
TBZ improves motor coordination performance of YAC128 HD mice
Design of TBZ trial in YAC128 mice.
Number of mice
Single dose (50 μl)
(three times per week)
Drug dosage (mg/kg)
50 μl PBS
50 μl PBS
0.125 mg of TBZ
(started at 2 months of age)
5 mg TBZ
0.125 mg of TBZ
(started at 6 months of age)
5 mg TBZ
50 μl PBS
50 μl PBS
0.125 mg of TBZ
(started at 2 months of age)
5 mg TBZ
0.125 mg of TBZ
(started at 6 months of age)
5 mg TBZ
The combined results from "rotarod" (Fig 1), "beam-walk" (Fig 2), and "gait walk" (Fig 3) behavioral analysis lead us to conclude that both "early" and "late" TBZ feeding significantly alleviates motor deficits developed by aging YAC128 mice.
Depression-related behaviors in TBZ-fed mice
TBZ protects against striatal cell loss in YAC128 HD mice
To obtain quantitative information about neuronal loss in these mice, the neuropathological assessments were performed by unbiased stereology as we previously described [30, 36]. The brains were fixed, frozen, and sliced with the microtome, and coronal sections corresponding to striatal region were stained with monoclonal antibodies against NeuN protein. Representative NeuN staining of striatal sections from each group of 13-month-old WT and YAC128 mice are shown on Fig 5B. The number of NeuN-positive neurons in the striatum was counted blindly with respect to the nature of the slices (genotype and drug treatment). By stereological analysis, we determined that control YAC128 mice showed significant striatal neuronal loss (p < 0.05) compared with control WT mice (Fig 5C). We further found that feeding of TBZ to WT mice did not cause significant changes in striatal neuronal counts in these mice (Fig 5C). However, TBZ feeding significantly increased striatal neuronal counts (p < 0.05) in YAC128 mice (Fig 5C), indicating that TBZ protects YAC128 MSNs from cell death. Brain weight and MSN cell numbers were not significantly different between Early-TBZ and Late-TBZ groups of YAC128 mice, with both groups showing similar degree of improvement when compared to control YAC128 group (Fig 5A, C). The results of our neuropathological analysis indicated that "early" and "late" feeding with TBZ significantly protected striatal neurons from cell death in aging YAC128 mice.
Striatum is the predominant target of midbrain dopaminergic neurons , and a number of experimental evidence point to a connection between dopamine signaling and MSN neurodegeneration in HD . Striatal MSN neurons expressing dopamine receptors in the striatum predominantly degenerate in HD patients, with cerebral cortex neurons being affected to a much lower extent, and striatal interneurons being spared [40, 41]. Biochemical analysis revealed progressive loss of striatal D1 and D2 receptors in post mortem HD brains [42–46]. Imaging studies also reported reduction of striatal D1 and D2 receptors in HD patients [13, 14] and in asymptomatic HD mutation carriers [15–19, 47, 48]. Consistent with analysis of human HD cases, drastic reduction of striatal D1 and D2 receptor density [19, 20] and deficiencies in D1 receptor-mediated signaling  were observed in R6/2 HD mouse model prior to onset of degeneration. In cellular models dopamine potentiates mutant huntingtin-mediated neurotoxicity by acting via D1-class [30, 31] and D2-class  dopamine receptors. The HD-like motor dysfunction and selective MSN degeneration have been observed in the dopamine transporter knockout mice . The hyperdopaminergic transmission accelerated formation of Httexp aggregates in 92Q knock-in HD mouse model . In our previous study we reported that feeding L-Dopa to YAC128 mice accelerated progression of the motor phenotype and increased neuronal loss in these mice . Most of these findings are consistent with an idea that dopamine exerts toxic effects on striatal neurons in the context of HD mutation, which leads in compensatory loss of D1 and D2 receptors in striatal region of HD brains.
Striatal MSN loss is the hallmark of HD. Increasing evidence suggested a permissive role of dopaminergic innervation of the striatum in the excitotoxicity in HD. Elevated glutamate-induced Ca2+ signals had been found to play an important role in HD , and dopamine could significantly potentiate glutamate-induced Ca2+ signals and MSN death in HD model , suggesting that glutamate and dopamine signaling pathways act synergistically to induce elevated Ca2+ signals and to cause apoptosis of HD MSNs . D1 class DARs are coupled to Ca2+ signalling via Gs/olf- cAMP-PKA, PKA activation modulates the glutamate-related Ca2+ signaling pathway by facilitating the activity of NMDAR [49, 50], AMPAR , and InsP3R1 [52, 53]. D2 class DARs directly coupled to Ca2+ signalling in MSNs via PLC activation. Therefore both D1 and D2 DARs might be involved in the potentiation effects of dopamine on elevated Ca2+ signalling and cell death in HD MSNs, and blockade of both D1 and D2 DARs would be necessary to exert significantly clinical beneficial effects for dopamine antagonist treatment in HD.
Ca2+ signalling is an important downstream in dopamine signalling cascades. In HD MSN, mutant Httexp potentiates the activity of NR2B NMDAR [8, 54–57] and InsP3R1 , which in turn causes abnormal function and cell death of HD MSN due to the disturbed Ca2+ signals. Thus over activation of Ca2+ signaling by mutant Httexp may lead to the compensatory loss of D1 and D2 receptors in striatal region of HD brains. Indeed, a significant reduction of striatal D1 and D2 receptors was found in PET imaging studies [13, 14] in HD patients and in HD mouse models [19–21]. The idea of the compensatory loss of D1 and D2 receptors are further supported by our rencent behavioral evaluation of dopamine tone in aging YAC128 HD mice (Wu at al, in preparation). Decreased denisty of striatal monoaminergic terminals was found in HD patients using DTBZ ((+)-alpha- [11C]dihydrotetrabenazine) PET imaging technique , suggesting the deficits of presynaptic dopamine innervation in HD. However, unlike the significant presynaptic nigrostriatal dopaminergic denervation in Parkinson's disease, Huntington's disease is characterized by more prominent striatal dopamine receptor loss, whereas nigrostriatal denervation is present to a lesser degree . We explain the decrease of dopaminergic inputs in HD as a compensatory effect of dopamine receptor loss in late stage of HD.
Tetrabenazine (TBZ) is a potent blocker of vesicular monoamine transporter (VMAT2). TBZ causes depletion of dopamine content in the presynaptic vesicles and reduction in the dopaminergic tone. In previous clinical trials TBZ has been shown to significantly reduce chorea symptoms in HD patients when compared with placebo group [32–35]. In our previous experiments with YAC128 mouse model we demonstarted that long term administration of TBZ (combined with L-Dopa) alleviated motor deficits and reduced striatal cell loss in these mice . These results indicated that TBZ and possibly other dopamine signaling antagonists may have a therapeutic potential for treatment of HD beyond previously established "symptomatic" benefit. In 2008 TBZ became the first drug officially approved by the Food and Drug administration for treatment of HD patients in the United States , greatly enhancing the need to carefully characterize actions of this drug in the context of HD models. We now repeated evaluation of TBZ in YAC128 model of HD and compared "early" (2 months) and "late" (6 months) treatment groups. We found that both "early" and "late" TBZ treatments alleviated the motor deficits (Figs 1, 2 and 3) and reduced striatal cell loss (Fig 5) in YAC128 mice, suggesting that treatment of both presymptomatic and early symptomatic HD patients with TBZ may have neuroprotective effects and delay progression of the disease. We should mentioned here that, TBZ is not a specific dopamine depleting agent, other neurotransmitter innervations such as serotoninergic and some noradrenergic may also play a role in this neuroprotective effects of TBZ.
By blocking VMAT2 TBZ depletes biogenic amines, including dopamine as well as serotonin and norepinephrine. Reduced levels of serotonin can cause depression. Indeed, it has been reported that many HD patients taking TBZ became severely depressed [32, 38]. Interestingly, we noticed that TBZ treatment groups of WT and YAC128 mice exhibited some symptoms of depression, such as hypoactivity and immobility in a tail suspension test. We performed a formal depression behavior analysis at 11 months of age for all 6 groups of mice by using forced-swim test (FST). In this analysis we discovered that both "early" and "late" TBZ treatment groups of WT and YAC128 mice appear to be depressed when compared to control groups (Fig 4). Thus, we concluded that TBZ is a useful therapeutic for treatment of HD, however prolonged treatment with TBZ induces depression. Additional dopamine antagonists which do not interfer with serotonin signaling system should be evaluated as potential HD therapeutics. The paradigms described in the present study can be used for evaluation of beneficial effects of these compounds for HD treatment as well as their ability to cause depression-like behaviors. A novel compound huntexil (pridopidine; ACR16) is a modulator of D2 receptor activity [61, 62] which has been recently developed by NeuroSearch for treatment of movement and psychiatric disorders. In recently completed phase III HD clinical trial (MermaiHD study), Huntexil demonstarted significant clinical benefit http://www.neurosearch.com/Default.aspx?ID=16&M=News&PID=12&NewsID=15886. Importantly, further analyisis of results of phase III trial suggested that Huntexil exerted not only symptomatic benefit but was also able to slow the underlying disease progression http://www.neurosearch.com/Default.aspx?ID=16&M=News&PID=12&NewsID=15894. These clinical findings with Huntexil are consistent with disease-modifying effects of TBZ that we observed in the present and previous studies with YAC128 HD mouse model (Fig 5 and ). It will be of interest to compare huntexil with TBZ and with other clinically relevant D1 and D2 receptor antagonists in YAC128 mouse model by following procedures described in the present report. Obtained results will provide opportunity to systematically compare symptomatic and disease modifying effects of these dopamine antagonists in HD, as well as evaluate potential side effects such as induction of depression.
Our present study demonstrated that TBZ, a dopamine signaling antagonist have therapeutic potential for treatment of HD beyond previously established "symptomatic" benefit. We found that both "early" and "late" TBZ treatments alleviated the motor deficits and reduced striatal cell loss in YAC128 mice, suggesting that treatment of both presymptomatic and early symptomatic HD patients with TBZ may have neuroprotective effects and delay progression of the disease. Moreover, we have been able to recapitulate and quantify depression-like symptoms in TBZ-treated mice, reminiscent of common side effects observed in HD patients taking TBZ, highlighting the need to develop and evaluate more specific dopamine antagonists for HD treatment.
Drug delivery in mice
All animal studies were approved by the University of Texas Southwestern Medical Center Animal Care and Use Committee. YAC128 mice (FVBN/NJ background strain)  were obtained from Jackson Labs (stock number 004938). Age-matched female wild type and YAC128 hemizygotous littermate mice were used in all our experiments. Tetrabenazine (TBZ) was obtained from Tocris, mixed with 2% cornflour using ceramic grinder and resuspended in PBS. TBZ was delivered to mice by oral feeding approach that we used in our previous studies with YAC128 mice . The drugs were fed orally to mice three times a week starting at 2 months of age. The mice were fed with 0.125 mg of TBZ suspended in 50 μl of PBS with 2% corn flour. To determine the efficacy of this drug delivery procedure, 7 wild-type mice of 2 months of age were fed orally with 0.125 mg of TBZ formulation and the blood samples were collected 30 minutes after drug feeding. The samples were diluted 1:1 in water for hemolyzation, flash frozen and shipped to Melior Discovery (Exton, PA) for quantitative analysis. The TBZ levels were analyzed using HPLC and compared with a standard TBZ sample. Data are expressed as average of the values from five samples ± SEM (see Results).
Motor coordination assessments in mice
The motor coordination experiments were performed as previously described [30, 36] with minor modifications. The "beam-walking" assay was performed using a home-built experimental setup. The 17 mm round beam, 11 mm round beam, and 5 mm square beam were used for training. At each time point (2, 6, 9, 11 and 13 months of age), the mice were trained to traverse the beam to the enclosed box. The mice were trained on 17 mm round beam for the 1st day, 11 mm round beam for the 2nd day, and 5 mm square beams for the 3rd day (two trials per day). Once the stable baseline of performance was obtained, the mice were tested in two consecutive trials on 11 mm round beam and then on 5 mm square beam, in each case progressing from the widest to the narrowest beam. The latency to traverse the middle section (80 cm in length) of each beam and the number of times the hind feet slipped off each beam were recorded for each trial. For each measurement, the mean scores of the two trials for each beam were used in the analysis.
The rotarod assessments were performed using Economex rotarod apparatus (Columbus Instruments, Columbus, OH) as previously described . At each time point, the mice were trained on the accelerating rotarod (accelerated from 0 to 40 rpm over 200 s) with 2 trials per day for 3 consecutive days, by which time a steady baseline level of performance was attained. The testing was executed over 1 day with 1.5 h of rest between tests. The mean latency to fall off the rotarod recorded in the two trials is used in analysis.
For the footprint test, the forepaws and hindpaws of the mice were coated with red and green nontoxic paints, respectively. The mice were trained to walk along a 50-cm-long, 10-cm-wide, paper-covered runway (with 10-cm-high walls) into an enclosed box. All the mice were given two runs per day for 3 consecutive days. A fresh sheet of white paper was placed on the floor of the runway for each run. The footprint patterns were assessed quantitatively by five measurements: stride length, hindbase width, frontbase width, front/hind footprint overlap and the ratio of hindbase and forebase as we previously described .
Forced swim test
Immobility in the forced swim test (FST) is a commonly used for measurement of depression in rodents [63–65]. Mice were individually placed into an individual glass beaker (54 cm in height and 24 cm in diameter) filled with room temperature water (23-25°C) to 40 cm depth. All test sessions were recorded for a total of 300 seconds by a video camera from the side of the cylinder. Total immobility time of each mouse after the first 120 seconds was manually scored by an experienced experimenter who was blinded to the genotype and drug treatment of the mice. Immobility was defined as the state in which mice were judged to be making only the movements necessary to keep their head above the surface.
Neuropathological assessments in mice
The neuropathological assessments were performed as previously described . At conclusion of behavioral testing (13 months time point), the mice were terminally anesthetized and perfused transcardially with 10 ml of 0.9% saline followed by 100 ml of fixative (4% paraformaldehyde in 0.1 M PBS, pH 7.4). All brains were removed from the skull, weighed, and transferred to postfixative overnight at 4°C in 4% paraformaldehyde and equilibrated in 20-30% (w/v) sucrose in PBS. The brains were processed and cut into 30-μm-thick coronal sections as described above. The coronal sections spaced 360 μm apart throughout the striatum (in the range from +1.70 mm to -2.30 mm relative to bregma) were stained with NeuN monoclonal antibody (1:1000 dilution; Millipore, Billerica, MA) and biotinylated anti-mouse secondary antibodies (1:200 dilution; Vector Laboratories, Burlington, Ontario, Canada) (M.O.M kit). Signal was amplified with an ABC Elite kit (Vector Laboratories) and detected with diaminobenzidine (Vector Laboratories). All quantitative stereological analyses were performed blindly with respect to the nature of slices (genotype and drug feeding) using Stereoinvestigator setup and software (MicroBrightField, Williston, VT). The grid size was set to 450 × 450 μm, and the counting frame was 50 × 50 μm. The average slice thickness after histological processing was determined to be 25 μm.
Statistical data analysis
The data were analyzed using SAS 9.13. The rotarod performance and beam-working performance were analyzed using 3 way ANOVA accounting for gene type (YAC128 vs wild type), drug treatment (PBS vs Early or Late-TBZ feeding) and animals age for all factor analysis, 2 way ANOVA for comparing treatment effects of Early or Late-TBZ feeding vs PBS control, or Early or Late-TBZ feeding in YAC128 and WT respectively, and 1 way ANOVA for age effects in animals treated with PBS alone. Tukey test or Student t test were also used where applicable.
We thank Xiangmei Kong for help with maintaining the YAC128 mouse colony and behavioral experiments, Leah Benson and Janet Young for administrative assistance, Shari Birnbaum for advice on forced swimming test experiments. IB is a holder of Carla Cocke Francis Professorship in Alzheimer's Research and supported by the CHDI foundation and NINDS R01 NS056224. TST is supported by the Knowledge Innovation Program of CAS, KSCX2-YW-R-148 and NSFC30970931.
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