Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease
Autor(a) principal: | |
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Data de Publicação: | 2015 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/51425 |
Resumo: | Machado-Joseph disease (MJD) is an inherited neurodegenerative disease, caused by a CAG repeat expansion within the coding region of ATXN3 gene, and which currently lacks effective treatment. In this work we tested the therapeutic efficacy of chronic treatment with valproic acid (VPA) (200mg/kg), a compound with known neuroprotection activity, and previously shown to be effective in cell, fly and nematode models of MJD. We show that chronic VPA treatment in the CMVMJD135 mouse model had limited effects in the motor deficits of these mice, seen mostly at late stages in the motor swimming, beam walk, rotarod and spontaneous locomotor activity tests, and did not modify the ATXN3 inclusion load and astrogliosis in affected brain regions. However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement. In spite of limited results, the use of another dosage of VPA or of VPA in a combined therapy with molecules targeting other pathways, cannot be excluded as potential strategies for MJD therapeutics |
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Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph diseaseCiências Médicas::Medicina ClínicaScience & TechnologyMachado-Joseph disease (MJD) is an inherited neurodegenerative disease, caused by a CAG repeat expansion within the coding region of ATXN3 gene, and which currently lacks effective treatment. In this work we tested the therapeutic efficacy of chronic treatment with valproic acid (VPA) (200mg/kg), a compound with known neuroprotection activity, and previously shown to be effective in cell, fly and nematode models of MJD. We show that chronic VPA treatment in the CMVMJD135 mouse model had limited effects in the motor deficits of these mice, seen mostly at late stages in the motor swimming, beam walk, rotarod and spontaneous locomotor activity tests, and did not modify the ATXN3 inclusion load and astrogliosis in affected brain regions. However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement. In spite of limited results, the use of another dosage of VPA or of VPA in a combined therapy with molecules targeting other pathways, cannot be excluded as potential strategies for MJD therapeuticsPM received funding from Ataxia UK Grant (Project: Pharmacologic therapy for Machado-Joseph disease: from a C. elegans drug screen to a mouse model validation). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersionPublic Library of Science (PLOS)Universidade do MinhoEsteves, SofiaSilva, Sara Carina DuarteNaia, LuanaCarvalho, Andreia Alexandra NevesCastro, Andreia Cristiana TeixeiraRego, Ana CristinaFernandes, Anabela SilvaMaciel, P.2015-10-212015-10-21T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/51425engEsteves, S., Duarte-Silva, S., Naia, L., Neves-Carvalho, A., Teixeira-Castro, A., Rego, A. C., ... & Maciel, P. (2015). Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease. PloS one, 10(10), e01416101932-620310.1371/journal.pone.014161026505994http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141610info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:10:23Zoai:repositorium.sdum.uminho.pt:1822/51425Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:01:58.958803Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease |
title |
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease |
spellingShingle |
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease Esteves, Sofia Ciências Médicas::Medicina Clínica Science & Technology |
title_short |
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease |
title_full |
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease |
title_fullStr |
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease |
title_full_unstemmed |
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease |
title_sort |
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease |
author |
Esteves, Sofia |
author_facet |
Esteves, Sofia Silva, Sara Carina Duarte Naia, Luana Carvalho, Andreia Alexandra Neves Castro, Andreia Cristiana Teixeira Rego, Ana Cristina Fernandes, Anabela Silva Maciel, P. |
author_role |
author |
author2 |
Silva, Sara Carina Duarte Naia, Luana Carvalho, Andreia Alexandra Neves Castro, Andreia Cristiana Teixeira Rego, Ana Cristina Fernandes, Anabela Silva Maciel, P. |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Esteves, Sofia Silva, Sara Carina Duarte Naia, Luana Carvalho, Andreia Alexandra Neves Castro, Andreia Cristiana Teixeira Rego, Ana Cristina Fernandes, Anabela Silva Maciel, P. |
dc.subject.por.fl_str_mv |
Ciências Médicas::Medicina Clínica Science & Technology |
topic |
Ciências Médicas::Medicina Clínica Science & Technology |
description |
Machado-Joseph disease (MJD) is an inherited neurodegenerative disease, caused by a CAG repeat expansion within the coding region of ATXN3 gene, and which currently lacks effective treatment. In this work we tested the therapeutic efficacy of chronic treatment with valproic acid (VPA) (200mg/kg), a compound with known neuroprotection activity, and previously shown to be effective in cell, fly and nematode models of MJD. We show that chronic VPA treatment in the CMVMJD135 mouse model had limited effects in the motor deficits of these mice, seen mostly at late stages in the motor swimming, beam walk, rotarod and spontaneous locomotor activity tests, and did not modify the ATXN3 inclusion load and astrogliosis in affected brain regions. However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement. In spite of limited results, the use of another dosage of VPA or of VPA in a combined therapy with molecules targeting other pathways, cannot be excluded as potential strategies for MJD therapeutics |
publishDate |
2015 |
dc.date.none.fl_str_mv |
2015-10-21 2015-10-21T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/51425 |
url |
http://hdl.handle.net/1822/51425 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Esteves, S., Duarte-Silva, S., Naia, L., Neves-Carvalho, A., Teixeira-Castro, A., Rego, A. C., ... & Maciel, P. (2015). Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease. PloS one, 10(10), e0141610 1932-6203 10.1371/journal.pone.0141610 26505994 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141610 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Public Library of Science (PLOS) |
publisher.none.fl_str_mv |
Public Library of Science (PLOS) |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799132420375576576 |