O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica.
Ano de defesa: | 2017 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , , |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Centro de Ciências da Saúde |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Farmacologia
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Departamento: |
Farmacologia
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País: |
Brasil
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Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/13769 |
Resumo: | Methylmalonic acidemia is an autosomal recessive metabolism biochemically characterized by a deficiency in the activity of the mutase methylmalonyl-CoA and the tissue accumulation of methylmalonate (MMA). In this acidemia, also occurs the accumulation of propionyl-CoA, which causes the inhibition of the metabolism of ammonia by urea cycle, leading to hyperammonemia. Clinically, this acidemia is characterized mainly by neurological disorders, including seizures and cognitive impairment. The data published in the article revealed that mice with acute treatment of MMA (0.66 mmol/2 uL) intracerebroventricularly (i.c.v) and an intermediate dose of NH 4 Cl (6 mmol/g) showed an increase in the duration of seizures induced by MMA. The administration of NH4Cl (6 mmol/g) also induced an increase of nitrite/nitrate (NOx), as well as the production of mitochondrial ROS over oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) DCFH, GS and followed by inhibition GAD. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na+,K+-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [3H] flunitrazepam binding, and GABA release after MMA injection. Since ammonia increased cerebral excitability of animals treated with MMA, it was objective this study to evaluate the ammonia role in development neural and glial of young mice after MMA administration, as well as to verify cognitive performance of these animals. The data presented in the manuscript demonstrated the results of MMA administration (2.5 μmol/g; injected intracisternally) or NaCl (2.5 μmol/g; i.c) on the first day of life and NH4Cl (7.5 mmol/g i.p.) or NaCl (0.9%; i.p.) on the second day of life of mice. From 21° to 33 ° or 40° to 52° days of age, the animals were evaluated for behavioral tasks such as radial maze test and high cross test. The levels of tumor necrosis factor-alpha (TNF-α), interleukin 1-betha, and DCFH were measured in cerebral cortex, striatum and hippocampus of mice with 21 and 40 days of life. The radial maze test showed that the animals injected with MMA and NH4Cl presented a worse performance in the working memory test, but not in the reference memory test in animals with 21 and 40 days of life. The animals showed no anxiety behavior. In addition, MMA and NH4Cl administration increased levels of TNF-α, DCFH in the cerebral cortex, hippocampus and striatum of mice with 21 and 40 days of life. The Interleukin 1β levels increased in cerebral cortex and striatum but not in hippocampus increased both in mice at 21 and 40 days of life.Considering the data presented, it is suggested that the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine/glutamate/GABA cycle and contribute to MMA-induced excitability. Furthermore, increased ROS production is related to an enhanced brain inflammatory process in a precocious period of development, leading to a learning delay in the animals treated with MMA. Thus, it is plausible to propose that ammonia contributes with cerebtral dysfunction in methylmalonic patients, favoring the appereance of neurological symptoms. |
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2018-07-12T20:41:53Z2018-07-12T20:41:53Z2017-08-29http://repositorio.ufsm.br/handle/1/13769Methylmalonic acidemia is an autosomal recessive metabolism biochemically characterized by a deficiency in the activity of the mutase methylmalonyl-CoA and the tissue accumulation of methylmalonate (MMA). In this acidemia, also occurs the accumulation of propionyl-CoA, which causes the inhibition of the metabolism of ammonia by urea cycle, leading to hyperammonemia. Clinically, this acidemia is characterized mainly by neurological disorders, including seizures and cognitive impairment. The data published in the article revealed that mice with acute treatment of MMA (0.66 mmol/2 uL) intracerebroventricularly (i.c.v) and an intermediate dose of NH 4 Cl (6 mmol/g) showed an increase in the duration of seizures induced by MMA. The administration of NH4Cl (6 mmol/g) also induced an increase of nitrite/nitrate (NOx), as well as the production of mitochondrial ROS over oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) DCFH, GS and followed by inhibition GAD. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na+,K+-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [3H] flunitrazepam binding, and GABA release after MMA injection. Since ammonia increased cerebral excitability of animals treated with MMA, it was objective this study to evaluate the ammonia role in development neural and glial of young mice after MMA administration, as well as to verify cognitive performance of these animals. The data presented in the manuscript demonstrated the results of MMA administration (2.5 μmol/g; injected intracisternally) or NaCl (2.5 μmol/g; i.c) on the first day of life and NH4Cl (7.5 mmol/g i.p.) or NaCl (0.9%; i.p.) on the second day of life of mice. From 21° to 33 ° or 40° to 52° days of age, the animals were evaluated for behavioral tasks such as radial maze test and high cross test. The levels of tumor necrosis factor-alpha (TNF-α), interleukin 1-betha, and DCFH were measured in cerebral cortex, striatum and hippocampus of mice with 21 and 40 days of life. The radial maze test showed that the animals injected with MMA and NH4Cl presented a worse performance in the working memory test, but not in the reference memory test in animals with 21 and 40 days of life. The animals showed no anxiety behavior. In addition, MMA and NH4Cl administration increased levels of TNF-α, DCFH in the cerebral cortex, hippocampus and striatum of mice with 21 and 40 days of life. The Interleukin 1β levels increased in cerebral cortex and striatum but not in hippocampus increased both in mice at 21 and 40 days of life.Considering the data presented, it is suggested that the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine/glutamate/GABA cycle and contribute to MMA-induced excitability. Furthermore, increased ROS production is related to an enhanced brain inflammatory process in a precocious period of development, leading to a learning delay in the animals treated with MMA. Thus, it is plausible to propose that ammonia contributes with cerebtral dysfunction in methylmalonic patients, favoring the appereance of neurological symptoms.Acidemia metilmalônica é um herança autossômica recessiva do metabolismo caracterizada bioquimicamente pela deficiência na atividade da metilmalonil-CoA mutase e pelo acúmulo tecidual de metilmalonato (MMA). Nesta acidemia, também ocorre o acúmulo de propionil-CoA, que causa a inibição do metabolismo da amônia pelo ciclo da uréia, levando a uma hiperamonemia. Clinicamente, esta acidemia caracteriza-se principalmente por alterações neurológicas, incluindo convulsões e déficit cognitivo.Os dados publicados no artigo I revelaram que os camundongos tratados com uma dose intermediária de NH4Cl (6 mmol/g; i.p.) apresentaram um aumento na duração das convulsões induzidas pelo MMA (0.66 μmol/2 μL; intracerebroventricular (i.c.v). A administração de NH4Cl (6 mmol/g) também induziu um aumento dos níveis de nitrito/nitrato (NOx) e a produção de ROS mitocondrial, avaliada através da oxidação de 2,7-diacetato de diclorofluoresceína (DCFH-DA) a DCFRS, assim como, induziu a inibição da atividade da glutamina sintetase (GS) e glutamato descarboxilase (GAD) no córtex cerebral dos animais. A administração de NH4Cl e MMA não apresentou alteração dos níveis de citocinas, alteração na permeabilidade da barreira hematoencefálica (BHE) ou dano neuronal nos animais. No entanto, a combinação dos dois tratamentos, aumentou os níveis de DCF-RS e atividade da Na+,K+-ATPase, reduziu o potencial mitocondrial (ΔΨ) e o MTT, assim como, inibiu a atividade da succinato desidrogenase (SDH) no córtex cerebral. A NH4Cl também alterou o ciclo de GABA caracterizado pela inibição da atividade da GS e GAD, ligação do [3H] flunitrazepam e liberação de GABA após a injeção de MMA. Com base nesses resultados, sugere-se que o aumento das espécies reativas de oxigênio e nitrogênio induzidos pela amônia alteraram o ciclo da glicina/glutamato/GABA e contribuíram para a excitabilidade induzida pelo MMA.Considerando que a amônia modificou a excitabilidade cerebral de animais adultos tratados com MMA, será objetivo desta tese também avaliar o papel da amônia no desenvolvimento cerebral e parâmetros inflamatórios e apoptóticos de animais jovens após a administração de MMA, assim como, a avaliação do desempenho cognitivo desses animais. Os dados apresentados no manuscrito descrevem os resultados da administração de MMA (2.5 μmol/g; intracisterna magna (i.c.m.) ou NaCl (2.5μmol/g; i.c.) no primeiro dia de vida e de NH4Cl (7.5 mmol/g; i.p.) ou NaCl (0.9%; i.p.) no segundo dia de vida em camundongos. A partir do 21° até 33° ou 40º até 52° dias de vida, os animais foram avaliados em tarefas comportamentais como o teste de labirinto radial e teste de cruz elevado. Os níveis de fator de necrose tumoral-alfa (TNF-α), interleucina 1β e DCF-RS, foram determinados no córtex cerebral, estriado e hipocampo de camundongos com 21 e 40 dias de vida. O teste do labirinto radial mostrou que os animais injetados com o MMA e NH4Cl apresentaram um pior desempenho no teste de memória de trabalho, mas não no teste de memória de referência com 21 e 40 dias de vida. Os animais não apresentaram comportamento de ansiedade com nenhum dos compostos testados. Entretanto, a administração de MMA e NH4Cl aumentou os níveis de TNF- α, DCFH no córtex cerebral, hipocampo e estriado dos camundongos com 21 e 40 dias de vida. Os níveis de interleucina 1β aumentaram no córtex cerebral e estriado, mas não aumentaram no hipocampo tanto em camundongos com 21 e 40 dias de vida.Considerando os dados apresentados, sugere-se que as mudanças no estado oxidativo induzido pela amônia alteram o ciclo glicina/glutamato/GABA, contribuindo com a excitabilidade do MMA e o aparecimento das convulsões. Além disso, a produção aumentada de ROS está associada a um aumento do processo inflamatório cerebral em um período precoce do desenvolvimento, conduzindo ao atraso de aprendizado nos animais tratados com MMA. Dessa forma, é plausível propor que amônia contribui com a disfunção cerebral nos pacientes com acidemia metilmalônica, favorecendo o aparecimento do quadro neurológico.porUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em FarmacologiaUFSMBrasilFarmacologiaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessÁcido metilmalônicoCamundongosConvulsõesMemóriaMorte neuronal e glialDano oxidativo e inflamatórioMethylmalonic acidMiceSeizuresMemoryNeuronal and glial deathOxidative damage and inflammatoryCNPQ::CIENCIAS DA SAUDE::FARMACIAO papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica.The role of ammonia on behavioral changes, neuroinflammation and apoptosis in an experimental model of methylmalonic acidemia.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisFighera, Michele Rechiahttp://lattes.cnpq.br/8583392747509231Premaor, Melissa Orlandinhttp://lattes.cnpq.br/1919693261808995Bresciani, Guilherme Bergamaschihttp://lattes.cnpq.br/1247251997170368Santos, Gabriela Trevisan doshttp://lattes.cnpq.br/7186082133291911http://lattes.cnpq.br/4407401588757466Gabbi, Patricia4003000000056008306e5eb-747a-45a0-a023-955603a45dcda128f970-16b0-45fa-bf05-d2767c4dc9f54a3f3e2c-bd56-4687-afe0-12304f1d95b603f335df-7f03-44d1-8866-576fb27afbe0621871da-e3cb-4a45-85b1-61ddfb6e0708reponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGFARMACOLOGIA_2017_GABBI_PATRICIA.pdfTES_PPGFARMACOLOGIA_2017_GABBI_PATRICIA.pdfTese de Doutoradoapplication/pdf1865301http://repositorio.ufsm.br/bitstream/1/13769/1/TES_PPGFARMACOLOGIA_2017_GABBI_PATRICIA.pdf611e4cbad570bbb34a7f998cee76a5f9MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica. |
dc.title.alternative.eng.fl_str_mv |
The role of ammonia on behavioral changes, neuroinflammation and apoptosis in an experimental model of methylmalonic acidemia. |
title |
O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica. |
spellingShingle |
O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica. Gabbi, Patricia Ácido metilmalônico Camundongos Convulsões Memória Morte neuronal e glial Dano oxidativo e inflamatório Methylmalonic acid Mice Seizures Memory Neuronal and glial death Oxidative damage and inflammatory CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica. |
title_full |
O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica. |
title_fullStr |
O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica. |
title_full_unstemmed |
O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica. |
title_sort |
O papel da amônia sobre as alterações comportamentais, neuroinflamação e apoptose em um modelo experimental de acidemia metilmalônica. |
author |
Gabbi, Patricia |
author_facet |
Gabbi, Patricia |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Fighera, Michele Rechia |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/8583392747509231 |
dc.contributor.referee1.fl_str_mv |
Premaor, Melissa Orlandin |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/1919693261808995 |
dc.contributor.referee2.fl_str_mv |
Bresciani, Guilherme Bergamaschi |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/1247251997170368 |
dc.contributor.referee3.fl_str_mv |
Santos, Gabriela Trevisan dos |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/7186082133291911 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/4407401588757466 |
dc.contributor.author.fl_str_mv |
Gabbi, Patricia |
contributor_str_mv |
Fighera, Michele Rechia Premaor, Melissa Orlandin Bresciani, Guilherme Bergamaschi Santos, Gabriela Trevisan dos |
dc.subject.por.fl_str_mv |
Ácido metilmalônico Camundongos Convulsões Memória Morte neuronal e glial Dano oxidativo e inflamatório |
topic |
Ácido metilmalônico Camundongos Convulsões Memória Morte neuronal e glial Dano oxidativo e inflamatório Methylmalonic acid Mice Seizures Memory Neuronal and glial death Oxidative damage and inflammatory CNPQ::CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Methylmalonic acid Mice Seizures Memory Neuronal and glial death Oxidative damage and inflammatory |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Methylmalonic acidemia is an autosomal recessive metabolism biochemically characterized by a deficiency in the activity of the mutase methylmalonyl-CoA and the tissue accumulation of methylmalonate (MMA). In this acidemia, also occurs the accumulation of propionyl-CoA, which causes the inhibition of the metabolism of ammonia by urea cycle, leading to hyperammonemia. Clinically, this acidemia is characterized mainly by neurological disorders, including seizures and cognitive impairment. The data published in the article revealed that mice with acute treatment of MMA (0.66 mmol/2 uL) intracerebroventricularly (i.c.v) and an intermediate dose of NH 4 Cl (6 mmol/g) showed an increase in the duration of seizures induced by MMA. The administration of NH4Cl (6 mmol/g) also induced an increase of nitrite/nitrate (NOx), as well as the production of mitochondrial ROS over oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) DCFH, GS and followed by inhibition GAD. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na+,K+-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [3H] flunitrazepam binding, and GABA release after MMA injection. Since ammonia increased cerebral excitability of animals treated with MMA, it was objective this study to evaluate the ammonia role in development neural and glial of young mice after MMA administration, as well as to verify cognitive performance of these animals. The data presented in the manuscript demonstrated the results of MMA administration (2.5 μmol/g; injected intracisternally) or NaCl (2.5 μmol/g; i.c) on the first day of life and NH4Cl (7.5 mmol/g i.p.) or NaCl (0.9%; i.p.) on the second day of life of mice. From 21° to 33 ° or 40° to 52° days of age, the animals were evaluated for behavioral tasks such as radial maze test and high cross test. The levels of tumor necrosis factor-alpha (TNF-α), interleukin 1-betha, and DCFH were measured in cerebral cortex, striatum and hippocampus of mice with 21 and 40 days of life. The radial maze test showed that the animals injected with MMA and NH4Cl presented a worse performance in the working memory test, but not in the reference memory test in animals with 21 and 40 days of life. The animals showed no anxiety behavior. In addition, MMA and NH4Cl administration increased levels of TNF-α, DCFH in the cerebral cortex, hippocampus and striatum of mice with 21 and 40 days of life. The Interleukin 1β levels increased in cerebral cortex and striatum but not in hippocampus increased both in mice at 21 and 40 days of life.Considering the data presented, it is suggested that the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine/glutamate/GABA cycle and contribute to MMA-induced excitability. Furthermore, increased ROS production is related to an enhanced brain inflammatory process in a precocious period of development, leading to a learning delay in the animals treated with MMA. Thus, it is plausible to propose that ammonia contributes with cerebtral dysfunction in methylmalonic patients, favoring the appereance of neurological symptoms. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017-08-29 |
dc.date.accessioned.fl_str_mv |
2018-07-12T20:41:53Z |
dc.date.available.fl_str_mv |
2018-07-12T20:41:53Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/13769 |
url |
http://repositorio.ufsm.br/handle/1/13769 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
400300000005 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
8306e5eb-747a-45a0-a023-955603a45dcd a128f970-16b0-45fa-bf05-d2767c4dc9f5 4a3f3e2c-bd56-4687-afe0-12304f1d95b6 03f335df-7f03-44d1-8866-576fb27afbe0 621871da-e3cb-4a45-85b1-61ddfb6e0708 |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Farmacologia |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Farmacologia |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações do UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Biblioteca Digital de Teses e Dissertações do UFSM |
collection |
Biblioteca Digital de Teses e Dissertações do UFSM |
bitstream.url.fl_str_mv |
http://repositorio.ufsm.br/bitstream/1/13769/1/TES_PPGFARMACOLOGIA_2017_GABBI_PATRICIA.pdf http://repositorio.ufsm.br/bitstream/1/13769/2/license_rdf http://repositorio.ufsm.br/bitstream/1/13769/3/license.txt http://repositorio.ufsm.br/bitstream/1/13769/4/TES_PPGFARMACOLOGIA_2017_GABBI_PATRICIA.pdf.txt http://repositorio.ufsm.br/bitstream/1/13769/5/TES_PPGFARMACOLOGIA_2017_GABBI_PATRICIA.pdf.jpg |
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MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações do UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
_version_ |
1793240168954593280 |