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https://hdl.handle.net/1822/78471
Título: | Aripiprazole 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-chave: | 5-HT (5-hydroxytryptamine; serotonin) Dopamine Machado-Joseph disease Spinocerebellar ataxia type 3 Antipsychotics Therapy 5-HT (5-hydroxytryptamine serotonin) |
Data: | 3-Fev-2022 |
Editora: | Multidisciplinary Digital Publishing Institute (MDPI) |
Revista: | Biomedicines |
Citação: | Jalles, 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. |
Tipo: | Artigo |
URI: | https://hdl.handle.net/1822/78471 |
DOI: | 10.3390/biomedicines10020370 |
e-ISSN: | 2227-9059 |
Versão da editora: | https://www.mdpi.com/2227-9059/10/2/370 |
Arbitragem científica: | yes |
Acesso: | Acesso aberto |
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Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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biomedicines-10-00370.pdf | 22,49 MB | Adobe PDF | Ver/Abrir |
Este trabalho está licenciado sob uma Licença Creative Commons