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

Molecular Neurobiology
Sofia EstevesPatrícia Maciel

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...Continue Reading

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Citations

Nov 7, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Jorge Diogo Da SilvaPatrícia Maciel
Sep 24, 2020·Expert Opinion on Therapeutic Targets·Andreia Neves-CarvalhoPatrícia Maciel
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Jul 14, 2020·Current Opinion in Neurology·Maria do Carmo Costa
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Sep 7, 2018·Molecular Neurobiology·Naila S AshrafMaria do Carmo Costa
Apr 11, 2020·Journal of Translational Medicine·Magda M SantanaLuís Pereira de Almeida
Sep 15, 2021·Journal of Neurochemistry·Urszula KozlowskaMaciej Figiel

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Methods Mentioned

BETA
transgenic
footprinting

Software Mentioned

Visiopharm integrator
Power
Chemidoc XRS Software
GraphPad
SPSS
ImageLab

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