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Antônio Carlos Pinheiro de Oliveirahttp://lattes.cnpq.br/2124700239916112http://lattes.cnpq.br/6402089315358170Soraya Wilke Saliba2023-07-06T17:25:25Z2023-07-06T17:25:25Z2014-05-22http://hdl.handle.net/1843/55894A doença de Huntington (DH) é uma patologia neurodegenerativa, autossômica dominante caracterizada por sintomas atribuídos à morte de neurônios estriatais e corticais. O mecanismo da neurodegeneração na DH parece estar relacionado com excitotoxicidade, disfunção mitocondrial e estresse oxidativo. A injeção intraestriatal de ácido quinolínico é conhecida por produzir alterações neuroquímicas e prejuízo motor similares à observada na DH. O processo excitotóxico pode induzir a produção de mediadores inflamatórios que são regulados por diversas vias de sinalização intracelular, como a via PI3K/mTOR. A ativação da via PI3K/mTOR participa da excitabilidade neuronal e captação de glutamato pelos astrócitos. No entanto, o papel exato de mTOR na excitotoxicidade atualmente não é compreendido. Assim, o objetivo deste estudo foi investigar os efeitos da inibição do mTOR contra os danos causados no estriado pelo administração única e unilateral de AQ (200 nmol) em camundongos. A rapamicina (0,2, 2, 20 µM/250 nL volume) foi injetada 15 minutos antes da administração de AQ e avaliados a alteração motora, neurodegeneração e ativação glial (astrócitos e microglia) depois de 2 dias da administração de AQ. Os mediadores inflamatórios e fatores neurotróficos foram avaliados após 8 horas da administração AQ. Uma única injeção de ácido quinolínico intraestriatal (200 nmol) diminuiu de forma significativa a coordenação motora, aumentou mediadores pro - inflamatórios (IL-1β, IL-6 e TNF-α) bem como aumentou a neurodegeneração no estriado ipsilateral quando comparado com o grupo controle negativo. Os resultados do tratamento farmacológico com rapamicina mostraram um perfil distinto entre as doses testadas. No parâmetro de produção de mediadores inflamatórios, todas as doses reverteram a expressão de citocinas pró inflamatórias e ainda a dose de 0,2 µM aumentou a expressão da citocina anti inflamatória, IL-10. Além disso, a menor dose de rapamicina reverteu a diminuição da marcação astrocitária induzida pela administração de AQ, além da melhora do perfil comportamental quando comparado ao grupo AQ. Os resultados do presente estudo demonstram que a inibição desta molécula reverte os efeitos excitotóxicos induzidos pela administração de AQ e sugerem o envolvimento de mTOR na patogenia da doença de Huntington.Huntington's disease (HD) is a autosomal dominant neurodegenerative disorder, characterized by symptoms attributed to the death of striatal and cortical neurons in the brain. The mechanism of neurodegeneration in HD seems to be related to excitotoxicity, oxidative stress and mitochondrial dysfunction. The intrastriatal injection of quinolinic acid is known to produce neurochemical alterations and motor impairment similar to that seen in Huntington's disease. The excitotoxic process may induce the production of inflammatory mediators that are regulated by several signaling pathways, such as activation of the PI3K/mTOR pathway. PI3K/mTOR pathway participates in neuronal excitability and glutamate uptake by astrocytes, events that may contribute to hyperexcitability and neuronal excitotoxicity. However, the exact role of mTOR in excitotoxicity is not currently understood. The objective of this study was to investigate the effects of mTOR inhibition against damage caused by striatal administration of single and unilateral QA (200 nmol) in mice .Rapamycin (0,2, 2, 20 µM/250 nL volume) was injected 15 minutes before the administration of QA and it was evaluated motility disorders, neurodegeneration and glial activation (astrocytes and microglia) 2 days after the administration of QA. Inflammatory mediators and neurotrophic factors were evaluated after 8 hours of QA administration. A single intrastriatal injection of QA (200 nmol) led to a significant decrease in motor coordination, increased mediators pro - inflammatory (IL-1β, IL-6 and TNF-α) and increased neurodegeneration in the ipsilateral striatum compared with the negative control group. The results of pharmacological treatment with rapamycin showed a distinct profile among the tested doses. In inflammatory parameter, all doses reversed the expression of pro - inflammatory cytokines and even the dose of 0.2 µM increased the expression of the anti-inflammatory cytokine IL-10. Furthermore, the lowest dose of rapamycin avoided the reduction of the astrocytic immunoreactivity induced by QA and reversed the motor impairment compared to the QA group. The results of this study provided evidence of the involvement of mTOR in the pathogenesis of Huntington's disease.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em Ciências Biológicas - Fisiologia e FarmacologiaUFMGBrasilICB - INSTITUTO DE CIÊNCIAS BIOLOGICAShttp://creativecommons.org/licenses/by-nc-nd/3.0/pt/info:eu-repo/semantics/openAccessDoença de HuntingtonRapamicinaÁcido quinolínicoInflamaçãoFator neurotróficoAlvo da rapamicina em mamíferosFisiologiaDoença de HuntingtonmTORRapamicinaÁcido quinolínicoInflamaçãoFatores neurotróficosAvaliação do efeito da rapamicina sobre a neuroinflamação e neurodegeneração em modelo de excitotoxicidade induzido por injeção intraestriatal de ácido quinolínicoinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALdissertacao_mestrado_soraya.pdfdissertacao_mestrado_soraya.pdfapplication/pdf2611894https://repositorio.ufmg.br/bitstream/1843/55894/1/dissertacao_mestrado_soraya.pdf3ec163aa4dca9359e8deba0eb5e6be83MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufmg.br/bitstream/1843/55894/2/license_rdfcfd6801dba008cb6adbd9838b81582abMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/55894/3/license.txtcda590c95a0b51b4d15f60c9642ca272MD531843/558942023-07-06 14:25:25.843oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-07-06T17:25:25Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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