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Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.

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Funding

This work was supported by National funds, through the Foundation for Science and Technology (Portugal) (FCT), under the scope of the projects PTDC/NEU-NMC/0248/2012, UID/DTP/04138/2013 and POCI-01-0145-FEDER-007038, and post-doctoral grants SFRH/BPD72891/2010 (to A.I.R.), SFRH/BPD/95855/2013 (to M.J.N.), SFRH/BPD/98023/2013 (to A.N.C.), SFRH/BPD/91562/2012 (to A.S.F.) and UMINHO/BI/248/2016 (to S.D.S.). This work has also been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and by FEDER funds, through the Competitiveness Factors Operational Program (COMPETE).

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Authors and Affiliations

  1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    Alexandra Isabel Rosa, Maria João Nunes, Andreia Neves Carvalho, Elsa Rodrigues, Maria João Gama, Cecília Maria Pereira Rodrigues & Margarida Castro-Caldas

  2. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal

    Sara Duarte-Silva, Anabela Silva-Fernandes & Patrícia Maciel

  3. ICVS/3B’s PT Government Associate Laboratory, University of Minho, Guimarães, Braga, Portugal

    Sara Duarte-Silva, Anabela Silva-Fernandes & Patrícia Maciel

  4. Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    Elsa Rodrigues, Maria João Gama & Cecília Maria Pereira Rodrigues

  5. Department of Life Sciences, Faculty of Science and Technology, Universidade NOVA de Lisboa, 2829-516, Caparica, Portugal

    Margarida Castro-Caldas

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  1. Alexandra Isabel Rosa
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Correspondence to Margarida Castro-Caldas.

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Alexandra Isabel Rosa and Sara Duarte-Silva are joint first authors.

Electronic Supplementary Material

Supplementary Figure 1

Motor performance evaluation of animals from the preclinical trial. (a) During behavioral assessment there were no differences in body weight variation between groups. Animal performance in the (b) square (12 mm) and in the (c) round (11 mm) beam tests, in the (d) Rotarod test and (e) Stride length determination. n = 14–17 for each group used. Data are presented as mean ± SD of the different groups. p.i. – days post-MPTP injection. (PPTX 335 kb)

Supplementary Figure 2

Time to reach the cage in the pole test. In the pole test, the time the animals took to reach the cage was determined. n = 14–17 for each group used. Data are presented as mean ± SD of the different groups. p.i. – days post-MPTP injection. (PPTX 125 kb)

Supplementary Table I

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Supplementary Table II

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Motor swimming test. This video shows the motor swimming performance of a vehicle-treated mouse. The perspex tank was 100 cm long and the platform at the end was made from black perspex. The latency to cross the water tank was measured from a distance of 60 cm (the tank was labeled with a blue line to mark the initiation). The water temperature was monitored to 23 °C using a thermostat. (MP4 7709 kb)

Motor swimming test. This video shows the motor swimming performance of a MPTP-treated mouse. The perspex tank was 100 cm long and the platform at the end was made from black perspex. The latency to cross the water tank was measured from a distance of 60 cm (the tank was labeled with a blue line to mark the initiation). The water temperature was monitored to 23 °C using a thermostat. (MP4 7752 kb)

Motor swimming test. This video shows the motor swimming performance of a mouse treated with TUDCA before MPTP injection. The perspex tank was 100 cm long and the platform at the end was made from black perspex. The latency to cross the water tank was measured from a distance of 60 cm (the tank was labeled with a blue line to mark the initiation). The water temperature was monitored to 23 °C using a thermostat. (MP4 6226 kb)

Motor swimming test. This video shows the motor swimming performance of a mouse injected with MPTP before TUDCA treatment. The perspex tank was 100 cm long and the platform at the end was made from black perspex. The latency to cross the water tank was measured from a distance of 60 cm (the tank was labeled with a blue line to mark the initiation). The water temperature was monitored to 23 °C using a thermostat. (MP4 10,192 kb)

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Rosa, A.I., Duarte-Silva, S., Silva-Fernandes, A. et al. Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson’s Disease. Mol Neurobiol 55, 9139–9155 (2018). https://doi.org/10.1007/s12035-018-1062-4

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