Utilize este identificador para referenciar este registo: https://hdl.handle.net/1822/78471

TítuloAripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans
Autor(es)Jalles, Ana
Vieira, Cármen Maria Leal
Pereira-Sousa, Joana
Campos, Daniela Vilasboas
Mota, Ana Francisca
Vasconcelos, Sara
Lomba, Bruna Melissa Ferreira
Costa, Marta Daniela Araújo
Silva, Jorge Diogo da
Maciel, P.
Castro, Andreia Cristiana Teixeira
Palavras-chave5-HT (5-hydroxytryptamine; serotonin)
Dopamine
Machado-Joseph disease
Spinocerebellar ataxia type 3
Antipsychotics
Therapy
5-HT (5-hydroxytryptamine
serotonin)
Data3-Fev-2022
EditoraMultidisciplinary Digital Publishing Institute (MDPI)
RevistaBiomedicines
CitaçãoJalles, A.; Vieira, C.; Pereira-Sousa, J.; Vilasboas-Campos, D.; Mota, A.F.; Vasconcelos, S.; Ferreira-Lomba, B.; Costa, M.D.; Da Silva, J.D.; Maciel, P.; Teixeira-Castro, A. Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans. Biomedicines 2022, 10, 370. https://doi.org/10.3390/biomedicines10020370
Resumo(s)The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D<sub>2</sub>-like and serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.
TipoArtigo
URIhttps://hdl.handle.net/1822/78471
DOI10.3390/biomedicines10020370
e-ISSN2227-9059
Versão da editorahttps://www.mdpi.com/2227-9059/10/2/370
Arbitragem científicayes
AcessoAcesso aberto
Aparece nas coleções:BUM - MDPI

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