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Preclinical Evidence Supporting Early Initiation of Citalopram Treatment in Machado-Joseph Disease

  • Sofia Esteves
  • Stéphanie Oliveira
  • Sara Duarte-Silva
  • Daniela Cunha-Garcia
  • Andreia Teixeira-Castro
  • Patrícia Maciel
Article

Abstract

Spinocerebellar ataxias are dominantly inherited neurodegenerative disorders with no disease-modifying treatment. We previously identified the selective serotonin reuptake inhibitor citalopram as a safe and effective drug to be repurposed for Machado-Joseph disease. Pre-symptomatic treatment of transgenic (CMVMJD135) mice strikingly ameliorated mutant ataxin-3 (ATXN3) pathogenesis. Here, we asked whether citalopram treatment initiated at a post-symptomatic age would still show efficacy. We used a cohort of CMVMJD135 mice that shows increased phenotypic severity and faster disease progression (CMVMJD135hi) compared to the mice used in the first trial. Groups of hemizygous CMVMJD135hi mice were orally treated with citalopram. Behavior, protein analysis, and pathology assessment were performed blindly to treatment. Our results show that even when initiated after symptom onset, treatment of CMVMJD135hi mice with citalopram ameliorated motor coordination and balance, attenuating disease progression, albeit to a lesser extent than that seen with pre-symptomatic treatment initiation. There was no impact on ATXN3 aggregation, which contrasts with the robust reduction in ATXN3-positive inclusions observed in CMVMJD135 mice, when treated pre-symptomatically. Post-symptomatic treatment of CMVMJD135hi mice revealed, however, a limited neuroprotective effect by showing a tendency to repair cerebellar calbindin staining, and to increase the number of motor neurons and of NeuN-positive cells in certain brain regions. While supporting that early initiation of treatment with citalopram leads to a marked increase in efficacy, these results strengthen our previous observation that modulation of serotonergic signaling by citalopram is a promising therapeutic approach for Machado-Joseph disease even after symptom onset.

Keywords

Spinocerebellar ataxia type 3 Selective serotonin reuptake inhibitor Citalopram Post-symptomatic treatment Transgenic model 

Abbreviations

5-HT

Serotonin

MJD

Machado-Joseph disease

SSRI

Selective serotonin reuptake inhibitor.

Notes

Acknowledgments

We are grateful to the members of the Maciel laboratory for sharing reagents and for critical analysis of the data and discussions on the manuscript. We thank members of the Morimoto lab for critical analysis of the results and figures. We also thank H. Lundbeck A/S for providing citalopram hydrobromide and Dr. Karina Fog for scientific discussions. We are grateful to Maria do Carmo Costa for critical review of the manuscript.

Author Contributions

SE, SO, AT-C, and PM contributed to the research project conception and organization. SE, SO, SD-S, DG-C, and AT-C performed the experiments. SE, SO, SD-S, and AT-C contributed to the statistical analysis design. SE, SO, and SD-S performed the statistical analysis. SE and AT-C wrote the first draft of the article. SO, SD-S, DG-C, AT-C, and PM reviewed and criticized the manuscript. All authors read and approved the final manuscript.

Funding

This work has been funded by the European Regional Development Funds (FEDER), through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the FEDER. This work was also supported by FCT and COMPETE through the projects [PTDC/SAU-GMG/112617/2009] (to PM) and [EXPL/BIM-MEC/0239/2012] (to AT-C), by FCT through the project [POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)] (to PM), by National Ataxia foundation (to PM and to AT-C), and by Ataxia UK (to PM). SE, SD-S, SO, and AT-C were supported by the FCT individual fellowships, SFRH/BD/78554/2011, SFRH/BD/78388/2011, PD/BD/127818/2016, and SFRH/BPD/102317/2014, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa, and EU/FSE.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1332_MOESM1_ESM.docx (809 kb)
ESM 1 (DOCX 808 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
  2. 2.ICVS/3B’s - PT Government Associate LaboratoryBraga/GuimarãesPortugal
  3. 3.Department of Molecular BiosciencesNorthwestern UniversityEvanstonUSA

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