Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | https://doi.org/10.1186/s12974-017-0793-x http://hdl.handle.net/1843/56257 https://orcid.org/0000-0002-0983-9422 https://orcid.org/0000-0003-3631-1989 https://orcid.org/0000-0002-9261-6771 https://orcid.org/0000-0002-3496-6749 https://orcid.org/0000-0002-9621-5422 https://orcid.org/0000-0003-3217-4294 |
Resumo: | Background: The mammalian target of rapamycin (mTOR) is a kinase involved in a variety of physiological and pathological functions. However, the exact role of mTOR in excitotoxicity is poorly understood. Here, we investigated the effects of mTOR inhibition with rapamycin against neurodegeneration, and motor impairment, as well as inflammatory profile caused by an excitotoxic stimulus. Methods: A single and unilateral striatal injection of quinolinic acid (QA) was used to induce excitotoxicity in mice. Rapamycin (250 nL of 0.2, 2, or 20 μM; intrastriatal route) was administered 15 min before QA injection. Forty-eight hours after QA administration, rotarod test was performed to evaluate motor coordination and balance. Fluoro-Jade C, Iba-1, and GFAP staining were used to evaluate neuronal cell death, microglia morphology, and astrocytes density, respectively, at this time point. Levels of cytokines and neurotrophic factors were measured by ELISA and Cytometric Bead Array 8 h after QA injection. Striatal synaptosomes were used to evaluate the release of glutamate. Results: We first demonstrated that rapamycin prevented the motor impairment induced by QA. Moreover, mTOR inhibition also reduced the neurodegeneration and the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α induced by excitotoxic stimulus. The lowest dose of rapamycin also increased the production of IL-10 and prevented the reduction of astrocyte density induced by QA. By using an in vitro approach, we demonstrated that rapamycin differently alters the release of glutamate from striatal synaptosomes induced by QA, reducing or enhancing the release of this neurotransmitter at low or high concentrations, respectively. Conclusion: Taken together, these data demonstrated a protective effect of rapamycin against an excitotoxic stimulus. Therefore, this study provides new evidence of the detrimental role of mTOR in neurodegeneration, which might represent an important target for the treatment of neurodegenerative diseases. |
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2023-07-14T19:34:51Z2023-07-14T19:34:51Z2017-01-3114https://doi.org/10.1186/s12974-017-0793-x1742-2094http://hdl.handle.net/1843/56257https://orcid.org/0000-0002-0983-9422https://orcid.org/0000-0003-3631-1989https://orcid.org/0000-0002-9261-6771https://orcid.org/0000-0002-3496-6749https://orcid.org/0000-0002-9621-5422https://orcid.org/0000-0003-3217-4294Background: The mammalian target of rapamycin (mTOR) is a kinase involved in a variety of physiological and pathological functions. However, the exact role of mTOR in excitotoxicity is poorly understood. Here, we investigated the effects of mTOR inhibition with rapamycin against neurodegeneration, and motor impairment, as well as inflammatory profile caused by an excitotoxic stimulus. Methods: A single and unilateral striatal injection of quinolinic acid (QA) was used to induce excitotoxicity in mice. Rapamycin (250 nL of 0.2, 2, or 20 μM; intrastriatal route) was administered 15 min before QA injection. Forty-eight hours after QA administration, rotarod test was performed to evaluate motor coordination and balance. Fluoro-Jade C, Iba-1, and GFAP staining were used to evaluate neuronal cell death, microglia morphology, and astrocytes density, respectively, at this time point. Levels of cytokines and neurotrophic factors were measured by ELISA and Cytometric Bead Array 8 h after QA injection. Striatal synaptosomes were used to evaluate the release of glutamate. Results: We first demonstrated that rapamycin prevented the motor impairment induced by QA. Moreover, mTOR inhibition also reduced the neurodegeneration and the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α induced by excitotoxic stimulus. The lowest dose of rapamycin also increased the production of IL-10 and prevented the reduction of astrocyte density induced by QA. By using an in vitro approach, we demonstrated that rapamycin differently alters the release of glutamate from striatal synaptosomes induced by QA, reducing or enhancing the release of this neurotransmitter at low or high concentrations, respectively. Conclusion: Taken together, these data demonstrated a protective effect of rapamycin against an excitotoxic stimulus. Therefore, this study provides new evidence of the detrimental role of mTOR in neurodegeneration, which might represent an important target for the treatment of neurodegenerative diseases.Antecedentes: O alvo mamífero da rapamicina (mTOR) é uma quinase envolvida em uma variedade de funções fisiológicas e patológicas. No entanto, o papel exato do mTOR na excitotoxicidade é pouco compreendido. Aqui, investigamos os efeitos da inibição de mTOR com rapamicina contra a neurodegeneração e comprometimento motor, bem como o perfil inflamatório causado por um estímulo excitotóxico. Métodos: Uma injeção estriatal única e unilateral de ácido quinolínico (QA) foi usada para induzir excitotoxicidade em camundongos. A rapamicina (250 nL de 0,2, 2 ou 20 μM; via intraestriatal) foi administrada 15 minutos antes da injeção de QA. Quarenta e oito horas após a administração do QA, foi realizado o teste do rotarod para avaliar a coordenação motora e o equilíbrio. As colorações de Fluoro-Jade C, Iba-1 e GFAP foram usadas para avaliar a morte celular neuronal, a morfologia da microglia e a densidade dos astrócitos, respectivamente, neste momento. Os níveis de citocinas e fatores neurotróficos foram medidos por ELISA e Cytometric Bead Array 8 h após a injeção de QA. Sinaptossomos estriados foram usados para avaliar a liberação de glutamato. Resultados: Primeiro demonstramos que a rapamicina preveniu o comprometimento motor induzido por QA. Além disso, a inibição de mTOR também reduziu a neurodegeneração e a produção de interleucina (IL)-1β, IL-6 e fator de necrose tumoral (TNF)-α induzida por estímulo excitotóxico. A menor dose de rapamicina também aumentou a produção de IL-10 e evitou a redução da densidade de astrócitos induzida por QA. Utilizando uma abordagem in vitro, demonstramos que a rapamicina altera de maneira diferente a liberação de glutamato dos sinaptossomas estriatais induzida por QA, reduzindo ou aumentando a liberação desse neurotransmissor em baixas ou altas concentrações, respectivamente. Conclusão: Tomados em conjunto, esses dados demonstraram um efeito protetor da rapamicina contra um estímulo excitotóxico. Portanto, este estudo fornece novas evidências do papel prejudicial do mTOR na neurodegeneração, o que pode representar um alvo importante para o tratamento de doenças neurodegenerativas.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas GeraisOutra AgênciaengUniversidade Federal de Minas GeraisUFMGBrasilICB - DEPARTAMENTO DE FARMACOLOGIAJournal of NeuroinflammationInibidores de MTORSirolimoSistema nervoso - DegeneraçãoÁcido quinolínicoInflamaçãoÁcido glutâmicoFatores de crescimento neuralNeurodegenerationmTORRapamycinQuinolinic acidInflammationGlutamateNeurotrophic factorsNeuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acidEfeitos neuroprotetores do intraestriatal injeção de rapamicina em um modelo de rato de excitotoxicidade induzida por ácido quinolínicoinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttps://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-0793-xSoraya Wilke SalibaErica Leandro Marciano VieiraRebeca Priscila de Melo SantosEduardo Candelario-JalilBernd L. FiebichLuciene Bruno VieiraAntônio Lúcio Teixeira JúniorAntônio Carlos Pinheiro de Oliveiraapplication/pdfinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGLICENSELicense.txtLicense.txttext/plain; charset=utf-82042https://repositorio.ufmg.br/bitstream/1843/56257/1/License.txtfa505098d172de0bc8864fc1287ffe22MD51ORIGINALNeuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid.pdfNeuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid.pdfapplication/pdf8155642https://repositorio.ufmg.br/bitstream/1843/56257/2/Neuroprotective%20effects%20of%20intrastriatal%20injection%20of%20rapamycin%20in%20a%20mouse%20model%20of%20excitotoxicity%20induced%20by%20quinolinic%20acid.pdf1be496c1dd0148f19a6a969d81277923MD521843/562572023-07-14 16:34:51.588oai:repositorio.ufmg.br:1843/56257TElDRU7vv71BIERFIERJU1RSSUJVSe+/ve+/vU8gTu+/vU8tRVhDTFVTSVZBIERPIFJFUE9TSVTvv71SSU8gSU5TVElUVUNJT05BTCBEQSBVRk1HCiAKCkNvbSBhIGFwcmVzZW50Ye+/ve+/vW8gZGVzdGEgbGljZW7vv71hLCB2b2Pvv70gKG8gYXV0b3IgKGVzKSBvdSBvIHRpdHVsYXIgZG9zIGRpcmVpdG9zIGRlIGF1dG9yKSBjb25jZWRlIGFvIFJlcG9zaXTvv71yaW8gSW5zdGl0dWNpb25hbCBkYSBVRk1HIChSSS1VRk1HKSBvIGRpcmVpdG8gbu+/vW8gZXhjbHVzaXZvIGUgaXJyZXZvZ++/vXZlbCBkZSByZXByb2R1emlyIGUvb3UgZGlzdHJpYnVpciBhIHN1YSBwdWJsaWNh77+977+9byAoaW5jbHVpbmRvIG8gcmVzdW1vKSBwb3IgdG9kbyBvIG11bmRvIG5vIGZvcm1hdG8gaW1wcmVzc28gZSBlbGV0cu+/vW5pY28gZSBlbSBxdWFscXVlciBtZWlvLCBpbmNsdWluZG8gb3MgZm9ybWF0b3Mg77+9dWRpbyBvdSB277+9ZGVvLgoKVm9j77+9IGRlY2xhcmEgcXVlIGNvbmhlY2UgYSBwb2zvv710aWNhIGRlIGNvcHlyaWdodCBkYSBlZGl0b3JhIGRvIHNldSBkb2N1bWVudG8gZSBxdWUgY29uaGVjZSBlIGFjZWl0YSBhcyBEaXJldHJpemVzIGRvIFJJLVVGTUcuCgpWb2Pvv70gY29uY29yZGEgcXVlIG8gUmVwb3NpdO+/vXJpbyBJbnN0aXR1Y2lvbmFsIGRhIFVGTUcgcG9kZSwgc2VtIGFsdGVyYXIgbyBjb250Ze+/vWRvLCB0cmFuc3BvciBhIHN1YSBwdWJsaWNh77+977+9byBwYXJhIHF1YWxxdWVyIG1laW8gb3UgZm9ybWF0byBwYXJhIGZpbnMgZGUgcHJlc2VydmHvv73vv71vLgoKVm9j77+9IHRhbWLvv71tIGNvbmNvcmRhIHF1ZSBvIFJlcG9zaXTvv71yaW8gSW5zdGl0dWNpb25hbCBkYSBVRk1HIHBvZGUgbWFudGVyIG1haXMgZGUgdW1hIGPvv71waWEgZGUgc3VhIHB1YmxpY2Hvv73vv71vIHBhcmEgZmlucyBkZSBzZWd1cmFu77+9YSwgYmFjay11cCBlIHByZXNlcnZh77+977+9by4KClZvY++/vSBkZWNsYXJhIHF1ZSBhIHN1YSBwdWJsaWNh77+977+9byDvv70gb3JpZ2luYWwgZSBxdWUgdm9j77+9IHRlbSBvIHBvZGVyIGRlIGNvbmNlZGVyIG9zIGRpcmVpdG9zIGNvbnRpZG9zIG5lc3RhIGxpY2Vu77+9YS4gVm9j77+9IHRhbWLvv71tIGRlY2xhcmEgcXVlIG8gZGVw77+9c2l0byBkZSBzdWEgcHVibGljYe+/ve+/vW8gbu+/vW8sIHF1ZSBzZWphIGRlIHNldSBjb25oZWNpbWVudG8sIGluZnJpbmdlIGRpcmVpdG9zIGF1dG9yYWlzIGRlIG5pbmd177+9bS4KCkNhc28gYSBzdWEgcHVibGljYe+/ve+/vW8gY29udGVuaGEgbWF0ZXJpYWwgcXVlIHZvY++/vSBu77+9byBwb3NzdWkgYSB0aXR1bGFyaWRhZGUgZG9zIGRpcmVpdG9zIGF1dG9yYWlzLCB2b2Pvv70gZGVjbGFyYSBxdWUgb2J0ZXZlIGEgcGVybWlzc++/vW8gaXJyZXN0cml0YSBkbyBkZXRlbnRvciBkb3MgZGlyZWl0b3MgYXV0b3JhaXMgcGFyYSBjb25jZWRlciBhbyBSZXBvc2l077+9cmlvIEluc3RpdHVjaW9uYWwgZGEgVUZNRyBvcyBkaXJlaXRvcyBhcHJlc2VudGFkb3MgbmVzdGEgbGljZW7vv71hLCBlIHF1ZSBlc3NlIG1hdGVyaWFsIGRlIHByb3ByaWVkYWRlIGRlIHRlcmNlaXJvcyBlc3Tvv70gY2xhcmFtZW50ZSBpZGVudGlmaWNhZG8gZSByZWNvbmhlY2lkbyBubyB0ZXh0byBvdSBubyBjb250Ze+/vWRvIGRhIHB1YmxpY2Hvv73vv71vIG9yYSBkZXBvc2l0YWRhLgoKQ0FTTyBBIFBVQkxJQ0Hvv73vv71PIE9SQSBERVBPU0lUQURBIFRFTkhBIFNJRE8gUkVTVUxUQURPIERFIFVNIFBBVFJPQ++/vU5JTyBPVSBBUE9JTyBERSBVTUEgQUfvv71OQ0lBIERFIEZPTUVOVE8gT1UgT1VUUk8gT1JHQU5JU01PLCBWT0Pvv70gREVDTEFSQSBRVUUgUkVTUEVJVE9VIFRPRE9TIEUgUVVBSVNRVUVSIERJUkVJVE9TIERFIFJFVklT77+9TyBDT01PIFRBTULvv71NIEFTIERFTUFJUyBPQlJJR0Hvv73vv71FUyBFWElHSURBUyBQT1IgQ09OVFJBVE8gT1UgQUNPUkRPLgoKTyBSZXBvc2l077+9cmlvIEluc3RpdHVjaW9uYWwgZGEgVUZNRyBzZSBjb21wcm9tZXRlIGEgaWRlbnRpZmljYXIgY2xhcmFtZW50ZSBvIHNldSBub21lKHMpIG91IG8ocykgbm9tZXMocykgZG8ocykgZGV0ZW50b3IoZXMpIGRvcyBkaXJlaXRvcyBhdXRvcmFpcyBkYSBwdWJsaWNh77+977+9bywgZSBu77+9byBmYXLvv70gcXVhbHF1ZXIgYWx0ZXJh77+977+9bywgYWzvv71tIGRhcXVlbGFzIGNvbmNlZGlkYXMgcG9yIGVzdGEgbGljZW7vv71hLgo=Repositório de PublicaçõesPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-07-14T19:34:51Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.pt_BR.fl_str_mv |
Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid |
dc.title.alternative.pt_BR.fl_str_mv |
Efeitos neuroprotetores do intraestriatal injeção de rapamicina em um modelo de rato de excitotoxicidade induzida por ácido quinolínico |
title |
Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid |
spellingShingle |
Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid Soraya Wilke Saliba Neurodegeneration mTOR Rapamycin Quinolinic acid Inflammation Glutamate Neurotrophic factors Inibidores de MTOR Sirolimo Sistema nervoso - Degeneração Ácido quinolínico Inflamação Ácido glutâmico Fatores de crescimento neural |
title_short |
Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid |
title_full |
Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid |
title_fullStr |
Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid |
title_full_unstemmed |
Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid |
title_sort |
Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid |
author |
Soraya Wilke Saliba |
author_facet |
Soraya Wilke Saliba Erica Leandro Marciano Vieira Rebeca Priscila de Melo Santos Eduardo Candelario-Jalil Bernd L. Fiebich Luciene Bruno Vieira Antônio Lúcio Teixeira Júnior Antônio Carlos Pinheiro de Oliveira |
author_role |
author |
author2 |
Erica Leandro Marciano Vieira Rebeca Priscila de Melo Santos Eduardo Candelario-Jalil Bernd L. Fiebich Luciene Bruno Vieira Antônio Lúcio Teixeira Júnior Antônio Carlos Pinheiro de Oliveira |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Soraya Wilke Saliba Erica Leandro Marciano Vieira Rebeca Priscila de Melo Santos Eduardo Candelario-Jalil Bernd L. Fiebich Luciene Bruno Vieira Antônio Lúcio Teixeira Júnior Antônio Carlos Pinheiro de Oliveira |
dc.subject.por.fl_str_mv |
Neurodegeneration mTOR Rapamycin Quinolinic acid Inflammation Glutamate Neurotrophic factors |
topic |
Neurodegeneration mTOR Rapamycin Quinolinic acid Inflammation Glutamate Neurotrophic factors Inibidores de MTOR Sirolimo Sistema nervoso - Degeneração Ácido quinolínico Inflamação Ácido glutâmico Fatores de crescimento neural |
dc.subject.other.pt_BR.fl_str_mv |
Inibidores de MTOR Sirolimo Sistema nervoso - Degeneração Ácido quinolínico Inflamação Ácido glutâmico Fatores de crescimento neural |
description |
Background: The mammalian target of rapamycin (mTOR) is a kinase involved in a variety of physiological and pathological functions. However, the exact role of mTOR in excitotoxicity is poorly understood. Here, we investigated the effects of mTOR inhibition with rapamycin against neurodegeneration, and motor impairment, as well as inflammatory profile caused by an excitotoxic stimulus. Methods: A single and unilateral striatal injection of quinolinic acid (QA) was used to induce excitotoxicity in mice. Rapamycin (250 nL of 0.2, 2, or 20 μM; intrastriatal route) was administered 15 min before QA injection. Forty-eight hours after QA administration, rotarod test was performed to evaluate motor coordination and balance. Fluoro-Jade C, Iba-1, and GFAP staining were used to evaluate neuronal cell death, microglia morphology, and astrocytes density, respectively, at this time point. Levels of cytokines and neurotrophic factors were measured by ELISA and Cytometric Bead Array 8 h after QA injection. Striatal synaptosomes were used to evaluate the release of glutamate. Results: We first demonstrated that rapamycin prevented the motor impairment induced by QA. Moreover, mTOR inhibition also reduced the neurodegeneration and the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α induced by excitotoxic stimulus. The lowest dose of rapamycin also increased the production of IL-10 and prevented the reduction of astrocyte density induced by QA. By using an in vitro approach, we demonstrated that rapamycin differently alters the release of glutamate from striatal synaptosomes induced by QA, reducing or enhancing the release of this neurotransmitter at low or high concentrations, respectively. Conclusion: Taken together, these data demonstrated a protective effect of rapamycin against an excitotoxic stimulus. Therefore, this study provides new evidence of the detrimental role of mTOR in neurodegeneration, which might represent an important target for the treatment of neurodegenerative diseases. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017-01-31 |
dc.date.accessioned.fl_str_mv |
2023-07-14T19:34:51Z |
dc.date.available.fl_str_mv |
2023-07-14T19:34:51Z |
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/1843/56257 |
dc.identifier.doi.pt_BR.fl_str_mv |
https://doi.org/10.1186/s12974-017-0793-x |
dc.identifier.issn.pt_BR.fl_str_mv |
1742-2094 |
dc.identifier.orcid.pt_BR.fl_str_mv |
https://orcid.org/0000-0002-0983-9422 https://orcid.org/0000-0003-3631-1989 https://orcid.org/0000-0002-9261-6771 https://orcid.org/0000-0002-3496-6749 https://orcid.org/0000-0002-9621-5422 https://orcid.org/0000-0003-3217-4294 |
url |
https://doi.org/10.1186/s12974-017-0793-x http://hdl.handle.net/1843/56257 https://orcid.org/0000-0002-0983-9422 https://orcid.org/0000-0003-3631-1989 https://orcid.org/0000-0002-9261-6771 https://orcid.org/0000-0002-3496-6749 https://orcid.org/0000-0002-9621-5422 https://orcid.org/0000-0003-3217-4294 |
identifier_str_mv |
1742-2094 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
Journal of Neuroinflammation |
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 |
Universidade Federal de Minas Gerais |
dc.publisher.initials.fl_str_mv |
UFMG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
ICB - DEPARTAMENTO DE FARMACOLOGIA |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
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Universidade Federal de Minas Gerais (UFMG) |
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UFMG |
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UFMG |
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