Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos
Ano de defesa: | 2019 |
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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 Naturais e Exatas |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica
|
Departamento: |
Bioquímica
|
País: |
Brasil
|
Palavras-chave em Português: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/21100 |
Resumo: | Alzheimer's Disease (AD) is a neurodegenerative disease that reaches about 47 million people in the world and this prevalence is expected to increase over the next two decades. A range of evidence has shown that the pathogenesis of AD is still not completely clear; it is heterogeneous and involves multiple factors. Ebselen is an organoselenium compound, which has pharmacological properties. In fact, the neuroprotective effects of ebselen have been recognized and their multifactorial targets appear to be an advantage for prospective therapeutic strategies. In addition, regular physical exercise has several benefits, among them improvement of cognitive aspects in the elderly. Therefore, the main objective of this study was to investigate the neuroprotective action of ebselen and the strength exercise in the pathophysiology of animal models of sporadic AD (CEUA: 7372110915 - 6145050717). Initially, the results of article 1 demonstrated that ebselen inhibited, in vitro. In the animal models of sporadic AD, ebselen (50 mg / kg via i.p.) inhibited IC50 33.14 (28.93 - 37.97) μM, the G4 isoform activity of the hippocampal enzyme acetylcholinesterase (AChE) showed a neuroprotective effect on a scopolamine-induced amnesia model, protecting against these deleterious effects in object recognition and Y-Maze behavioral tests in Swiss mice. In addition, this compound inhibited AChE activity in the hippocampus of mice. These results suggest that ebselen modulated dysfunction in scopolamine-induced cholinergic neurotransmission. In article 2 the experimental protocol, repeated treatment with lower doses of ebselen (1 and 10 mg/kg via i.p.) in a model of AD induced by streptozotocin (STZ - 3 mg / kg via i.c.v.) was carried out. Ebselen treatment was effective in reversing the memory loss caused by STZ in mice, which was demonstrated in the object recognition and location tests and Y-Maze. In addition, the compound was effective in reversing all parameters of oxidative stress and protein levels of the apoptotic pathway in the Bax/Bcl-2, cleaved PARP/PARP ratios and caspase-3 levels in the hippocampus of STZ-treated mice. In the manuscript I mice were subjected to a non-pharmacological therapeutic treatment, a strength exercise program, which was carried out bin a ladder, where the animals underwent progressive force training (4 weeks). Strength exercise increased levels of neurogenic markers via BDNF/ERK-CAMK-II/CREB signaling in the hippocampus of mice, in addition to suppressing memory loss in the Morris water maze (MWM) test in a sporadic AD model. Finally, this thesis contributes to better understand the neuroprotective mechanisms involved in the action of ebselen and reinforces the hypothesis that this compound may be an interesting therapeutic alternative for the treatment of AD. Regarding strength exercise, the results help to understand the effects of strength exercise on AD. |
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2021-06-09T20:44:23Z2021-06-09T20:44:23Z2019-02-22http://repositorio.ufsm.br/handle/1/21100Alzheimer's Disease (AD) is a neurodegenerative disease that reaches about 47 million people in the world and this prevalence is expected to increase over the next two decades. A range of evidence has shown that the pathogenesis of AD is still not completely clear; it is heterogeneous and involves multiple factors. Ebselen is an organoselenium compound, which has pharmacological properties. In fact, the neuroprotective effects of ebselen have been recognized and their multifactorial targets appear to be an advantage for prospective therapeutic strategies. In addition, regular physical exercise has several benefits, among them improvement of cognitive aspects in the elderly. Therefore, the main objective of this study was to investigate the neuroprotective action of ebselen and the strength exercise in the pathophysiology of animal models of sporadic AD (CEUA: 7372110915 - 6145050717). Initially, the results of article 1 demonstrated that ebselen inhibited, in vitro. In the animal models of sporadic AD, ebselen (50 mg / kg via i.p.) inhibited IC50 33.14 (28.93 - 37.97) μM, the G4 isoform activity of the hippocampal enzyme acetylcholinesterase (AChE) showed a neuroprotective effect on a scopolamine-induced amnesia model, protecting against these deleterious effects in object recognition and Y-Maze behavioral tests in Swiss mice. In addition, this compound inhibited AChE activity in the hippocampus of mice. These results suggest that ebselen modulated dysfunction in scopolamine-induced cholinergic neurotransmission. In article 2 the experimental protocol, repeated treatment with lower doses of ebselen (1 and 10 mg/kg via i.p.) in a model of AD induced by streptozotocin (STZ - 3 mg / kg via i.c.v.) was carried out. Ebselen treatment was effective in reversing the memory loss caused by STZ in mice, which was demonstrated in the object recognition and location tests and Y-Maze. In addition, the compound was effective in reversing all parameters of oxidative stress and protein levels of the apoptotic pathway in the Bax/Bcl-2, cleaved PARP/PARP ratios and caspase-3 levels in the hippocampus of STZ-treated mice. In the manuscript I mice were subjected to a non-pharmacological therapeutic treatment, a strength exercise program, which was carried out bin a ladder, where the animals underwent progressive force training (4 weeks). Strength exercise increased levels of neurogenic markers via BDNF/ERK-CAMK-II/CREB signaling in the hippocampus of mice, in addition to suppressing memory loss in the Morris water maze (MWM) test in a sporadic AD model. Finally, this thesis contributes to better understand the neuroprotective mechanisms involved in the action of ebselen and reinforces the hypothesis that this compound may be an interesting therapeutic alternative for the treatment of AD. Regarding strength exercise, the results help to understand the effects of strength exercise on AD.Sabe-se que a Doença de Alzheimer (DA) é uma doença neurodegenerativa que atinge cerca de 47 milhões de pessoas no mundo. Este número está previsto para aumentar nas próximas duas décadas. Uma gama de evidências tem mostrado que a patogênese da DA ainda não está completamente clara, afirma-se que seja heterogênea, pois seu desencadeamento está relacionado com o envolvimento de múltiplos fatores. O ebselen é um composto orgânico de selênio, que tem merecido destaque na literatura devido suas propriedades farmacológicas. De fato, os efeitos neuroprotetores do ebselen foram reconhecidos e seus alvos multifatoriais parecem ser uma vantagem para estratégias terapêuticas prospectivas. Ainda, a prática de exercício físico regular proporciona diversos benefícios, e um deles está associado a aspectos cognitivos, em idosos. Com isso, o objetivo principal desse estudo foi investigar a ação neuroprotetora do composto ebselen e do exercício de força na fisiopatologia da doença de Alzheimer em modelos animais de DA esporádica (CEUA: 7372110915 – 6145050717). Inicialmente, os resultados do artigo 1 demonstraram que o ebselen inibiu, IC50 33.14 (28.93 – 37.97) µM, a atividade da isoforma G4 da enzima acetilcolinesterase (AChE) hipocampal, in vitro. Nos modelos animais da DA esporádica, o ebselen (50mg/kg via i.p.) mostrou um efeito neuroprotetor em um modelo de amnésia induzida pela escopolamina, protegendo desses efeitos deletérios nos testes comportamentais de reconhecimento do objeto e Y- Maze em camundongos Swiss. Somado a isso, este composto apresentou uma inibição na atividade da AChE, no hipocampo dos camundongos. Estes resultados sugerem que o ebselen modulou a disfunção na neurotransmissão colinérgica induzida pela escopolamina. No artigo 2 o protocolo experimental utilizando estreptozotocina (ETZ - 3 mg/kg via i.c.v.) visou um tratamento terapêutico e repetido com doses mais baixas de ebselen (1 e 10 mg/kg via i.p.). O tratamento com ebselen, nos camundongos, em doses baixas, foi eficaz em reverter a perda de memória ocasionada pela no teste de reconhecimento e localização do objeto e no Y-Maze. Além disso, o composto foi efetivo em reverter todos os parâmetros de estresse oxidativo e os níveis de proteínas da via apoptótica nas razões de Bax/Bcl-2, PARP clivada/PARP e nos níveis de caspase-3 no hipocampo de camundongos tratados com ETZ. O manuscrito I visou um tratamento terapêutico não farmacológico com um programa de exercício de força utilizando uma escada, onde os animais foram submetidos a um treino de força progressiva com duração de 4 semanas. O exercício de força aumentou os níveis de marcadores neurogênicos via sinalização BDNF/ERK-CAMK-II/CREB no hipocampo de camundongos, além de suprimir a perda de memória no teste do Morris water maze (MWM), em um modelo de DA esporádica. Finalmente, esta tese contribui para o esclarecimento dos mecanismos neuroprotetores envolvidos na ação do ebselen e reforça a hipótese de que composto pode ser uma interessante alternativa terapêutica para o tratamento da DA. Ainda, com relação ao exercício físico de força, os resultados contribuem para o entendimento dos efeitos do exercício de força sobre a DA.porUniversidade Federal de Santa MariaCentro de Ciências Naturais e ExatasPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBrasilBioquímicaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessEbselenExercício de forçaAlzheimerNeuroproteçãoEstresse oxidativoEstresse oxidativoCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAAção neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongosNeuroprotective action of ebselen compound and physical exercise in sporadic Alzheimer disease models in miceinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisNogueira, Cristina Waynehttp://lattes.cnpq.br/2877042401245169Spanevello, Roselia MariaXXXXXXXXXXXXXXXSagrillo, Michele RoratoXXXXXXXXXXXXXXXXXXSimonetti, CamilaXXXXXXXXXXXXXXXStefanello, FrancieliXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXMartini, Franciele2008000000026000186436d-f662-4a5e-b36e-8c8ab8e10bf8fc1071ad-851c-4046-b96e-37c7baf52a7f2c5b3e7b-5bee-4ab4-92a9-97c6a36565e31998b090-e036-483d-8880-138523b412bcb1b98fe7-f6f8-4b8e-971f-9059c4521128a5aa85f4-24c3-4dab-b858-8514fda0633breponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGBT_2019_MARTINI_FRANCIELE.pdfTES_PPGBT_2019_MARTINI_FRANCIELE.pdfTese de Doutoradoapplication/pdf20695736http://repositorio.ufsm.br/bitstream/1/21100/1/TES_PPGBT_2019_MARTINI_FRANCIELE.pdfb12d2df6eeeb2a4e6c8650d6e3dd103aMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos |
dc.title.alternative.eng.fl_str_mv |
Neuroprotective action of ebselen compound and physical exercise in sporadic Alzheimer disease models in mice |
title |
Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos |
spellingShingle |
Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos Martini, Franciele Ebselen Exercício de força Alzheimer Neuroproteção Estresse oxidativo Estresse oxidativo CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos |
title_full |
Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos |
title_fullStr |
Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos |
title_full_unstemmed |
Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos |
title_sort |
Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos |
author |
Martini, Franciele |
author_facet |
Martini, Franciele |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Nogueira, Cristina Wayne |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2877042401245169 |
dc.contributor.referee1.fl_str_mv |
Spanevello, Roselia Maria |
dc.contributor.referee1Lattes.fl_str_mv |
XXXXXXXXXXXXXXX |
dc.contributor.referee2.fl_str_mv |
Sagrillo, Michele Rorato |
dc.contributor.referee2Lattes.fl_str_mv |
XXXXXXXXXXXXXXXXXX |
dc.contributor.referee3.fl_str_mv |
Simonetti, Camila |
dc.contributor.referee3Lattes.fl_str_mv |
XXXXXXXXXXXXXXX |
dc.contributor.referee4.fl_str_mv |
Stefanello, Francieli |
dc.contributor.referee4Lattes.fl_str_mv |
XXXXXXXXXXXXXXXXXX |
dc.contributor.authorLattes.fl_str_mv |
XXXXXXXXXXXXXXXX |
dc.contributor.author.fl_str_mv |
Martini, Franciele |
contributor_str_mv |
Nogueira, Cristina Wayne Spanevello, Roselia Maria Sagrillo, Michele Rorato Simonetti, Camila Stefanello, Francieli |
dc.subject.por.fl_str_mv |
Ebselen Exercício de força Alzheimer Neuroproteção Estresse oxidativo Estresse oxidativo |
topic |
Ebselen Exercício de força Alzheimer Neuroproteção Estresse oxidativo Estresse oxidativo CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Alzheimer's Disease (AD) is a neurodegenerative disease that reaches about 47 million people in the world and this prevalence is expected to increase over the next two decades. A range of evidence has shown that the pathogenesis of AD is still not completely clear; it is heterogeneous and involves multiple factors. Ebselen is an organoselenium compound, which has pharmacological properties. In fact, the neuroprotective effects of ebselen have been recognized and their multifactorial targets appear to be an advantage for prospective therapeutic strategies. In addition, regular physical exercise has several benefits, among them improvement of cognitive aspects in the elderly. Therefore, the main objective of this study was to investigate the neuroprotective action of ebselen and the strength exercise in the pathophysiology of animal models of sporadic AD (CEUA: 7372110915 - 6145050717). Initially, the results of article 1 demonstrated that ebselen inhibited, in vitro. In the animal models of sporadic AD, ebselen (50 mg / kg via i.p.) inhibited IC50 33.14 (28.93 - 37.97) μM, the G4 isoform activity of the hippocampal enzyme acetylcholinesterase (AChE) showed a neuroprotective effect on a scopolamine-induced amnesia model, protecting against these deleterious effects in object recognition and Y-Maze behavioral tests in Swiss mice. In addition, this compound inhibited AChE activity in the hippocampus of mice. These results suggest that ebselen modulated dysfunction in scopolamine-induced cholinergic neurotransmission. In article 2 the experimental protocol, repeated treatment with lower doses of ebselen (1 and 10 mg/kg via i.p.) in a model of AD induced by streptozotocin (STZ - 3 mg / kg via i.c.v.) was carried out. Ebselen treatment was effective in reversing the memory loss caused by STZ in mice, which was demonstrated in the object recognition and location tests and Y-Maze. In addition, the compound was effective in reversing all parameters of oxidative stress and protein levels of the apoptotic pathway in the Bax/Bcl-2, cleaved PARP/PARP ratios and caspase-3 levels in the hippocampus of STZ-treated mice. In the manuscript I mice were subjected to a non-pharmacological therapeutic treatment, a strength exercise program, which was carried out bin a ladder, where the animals underwent progressive force training (4 weeks). Strength exercise increased levels of neurogenic markers via BDNF/ERK-CAMK-II/CREB signaling in the hippocampus of mice, in addition to suppressing memory loss in the Morris water maze (MWM) test in a sporadic AD model. Finally, this thesis contributes to better understand the neuroprotective mechanisms involved in the action of ebselen and reinforces the hypothesis that this compound may be an interesting therapeutic alternative for the treatment of AD. Regarding strength exercise, the results help to understand the effects of strength exercise on AD. |
publishDate |
2019 |
dc.date.issued.fl_str_mv |
2019-02-22 |
dc.date.accessioned.fl_str_mv |
2021-06-09T20:44:23Z |
dc.date.available.fl_str_mv |
2021-06-09T20:44:23Z |
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/1/21100 |
url |
http://repositorio.ufsm.br/handle/1/21100 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
200800000002 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
0186436d-f662-4a5e-b36e-8c8ab8e10bf8 fc1071ad-851c-4046-b96e-37c7baf52a7f 2c5b3e7b-5bee-4ab4-92a9-97c6a36565e3 1998b090-e036-483d-8880-138523b412bc b1b98fe7-f6f8-4b8e-971f-9059c4521128 a5aa85f4-24c3-4dab-b858-8514fda0633b |
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 Naturais e Exatas |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Bioquímica |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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/1/21100/1/TES_PPGBT_2019_MARTINI_FRANCIELE.pdf http://repositorio.ufsm.br/bitstream/1/21100/2/license_rdf http://repositorio.ufsm.br/bitstream/1/21100/3/license.txt http://repositorio.ufsm.br/bitstream/1/21100/4/TES_PPGBT_2019_MARTINI_FRANCIELE.pdf.txt http://repositorio.ufsm.br/bitstream/1/21100/5/TES_PPGBT_2019_MARTINI_FRANCIELE.pdf.jpg |
bitstream.checksum.fl_str_mv |
b12d2df6eeeb2a4e6c8650d6e3dd103a 4460e5956bc1d1639be9ae6146a50347 2f0571ecee68693bd5cd3f17c1e075df f7bc6a2631a4ecc45e73b239694db85d 863589e3d72a0f5f8c6462c47626d014 |
bitstream.checksumAlgorithm.fl_str_mv |
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 |
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1793240121384894464 |