N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens
Autor(a) principal: | |
---|---|
Data de Publicação: | 2014 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional Manancial UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/11227 |
Resumo: | Glutaric aciduria type I (GA-I) is an inborn error of metabolism (EIM) characterized biochemically by accumulation of glutaric acid (GA). The clinical manifestations are mainly neurological and develop during childhood. Among these changes, there are the seizures and cognitive deficits, which may be precipitated by infectious processes. Although growing evidence supports that inflammation and oxidative damage are both involved in learning impairment, it is not known whether inflammatory and oxidative stress markers facilitate GA-induced memory impairment. From this, the main objective of this study was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test on Barnes maze. To evaluate antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. Furthermore, we also evaluated wheter N-acetylcysteine (NAC) could improve these behavioral, biochemical or structural changes induced by GA and LPS administration. For this, the rat pups were injected with GA (5umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). In order to mimic a severe infection state, LPS (2 mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life.Oxidative stress biomarkers, antioxidant activity and hippocampal volume were assessed. In this study, GA caused spatial learning deficit in the Barnes maze, and that LPS potentiated the memory impairment induced by GA in rat pups. In addition, GA and LPS increased proinflammatory cytokine levels (TNF- and IL-1), and the co-administration of these compounds potentiated the increase of IL-1 levels but not TNF- levels in the hippocampus of this animals. Although GA and LPS administration increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+,K+-ATPase activity (total and subunit α1), GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. N-acetylcysteine protected against impairment of spatial learning and increase of cytokines levels induced by GA and LPS. The NAC also protected against deleterious effects induced by GA and LPS, as characterized by inhibition of Na+,K+-ATPase activity (total and subunit α1)and increase of TBARS content, as well as the reduction of antioxidant defenses(non protein thiols and glutathione content, superoxide dismutase and catalase activities).These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Pharmacological protection with NAC during encephalopatic crises could be considered as an adjuvant therapy to prevent hippocampal dysfunction and the progression of disease in children with GA-I. |
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2015-03-042015-03-042014-03-10RODRIGUES, Fernanda Silva. N-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pups. 2014. 83 f. Dissertação (Mestrado em Ciências Biológicas) - Universidade Federal de Santa Maria, Santa Maria, 2014.http://repositorio.ufsm.br/handle/1/11227Glutaric aciduria type I (GA-I) is an inborn error of metabolism (EIM) characterized biochemically by accumulation of glutaric acid (GA). The clinical manifestations are mainly neurological and develop during childhood. Among these changes, there are the seizures and cognitive deficits, which may be precipitated by infectious processes. Although growing evidence supports that inflammation and oxidative damage are both involved in learning impairment, it is not known whether inflammatory and oxidative stress markers facilitate GA-induced memory impairment. From this, the main objective of this study was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test on Barnes maze. To evaluate antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. Furthermore, we also evaluated wheter N-acetylcysteine (NAC) could improve these behavioral, biochemical or structural changes induced by GA and LPS administration. For this, the rat pups were injected with GA (5umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). In order to mimic a severe infection state, LPS (2 mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life.Oxidative stress biomarkers, antioxidant activity and hippocampal volume were assessed. In this study, GA caused spatial learning deficit in the Barnes maze, and that LPS potentiated the memory impairment induced by GA in rat pups. In addition, GA and LPS increased proinflammatory cytokine levels (TNF- and IL-1), and the co-administration of these compounds potentiated the increase of IL-1 levels but not TNF- levels in the hippocampus of this animals. Although GA and LPS administration increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+,K+-ATPase activity (total and subunit α1), GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. N-acetylcysteine protected against impairment of spatial learning and increase of cytokines levels induced by GA and LPS. The NAC also protected against deleterious effects induced by GA and LPS, as characterized by inhibition of Na+,K+-ATPase activity (total and subunit α1)and increase of TBARS content, as well as the reduction of antioxidant defenses(non protein thiols and glutathione content, superoxide dismutase and catalase activities).These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Pharmacological protection with NAC during encephalopatic crises could be considered as an adjuvant therapy to prevent hippocampal dysfunction and the progression of disease in children with GA-I.A acidemia glutrárica do tipo I (AG-I) é um erro inato do metabolismo (EIM) caracterizada bioquimicamente pelo pelo acúmulo de ácido glutárico (AG). As manifestações clínicas são predominantemente neurológicas, e desenvolvem-se principalmente na infância. Entre essas alterações, as quais são precipitadas por processos infecciosos, pode-se citar o déficit cognitivo. Embora estudos recentes sugerem que a inflamação e o estresse oxidativo estão envolvidos no déficit cognitivo, não se sabe se os marcadores inflamatórios e oxidativos facilitam o prejuízo de memória após a administração de AG. A partir disso, o objetivo desta dissertação foi investigar o desempenho de ratos jovens injetados cronicamente com AG e lipopolissacarídeo (LPS) no teste de memória espacial no labirinto de Barnes. Além disso, foi avaliado os níveis das defesas antioxidantes, níveis de citocinas, atividade da enzima Na+, K+-ATPase e volume hipocampal. Como a N-acetilcisteína (NAC) possui propriedades antioxidantes e antiinflamatórias, foi testado se esse composto poderia melhorar as alterações comportamentais, bioquímicas e estruturais induzidas pela administração de AG e LPS. Para isso, os ratos jovens foram injetados com AG (5 μmol/g do peso corporal-1; subcutaneamente; duas vezes por dia; do 5º ao 28º dia de vida), e foram suplementados com NAC (150 mg/kg/dia; por gavagem; pelo mesmo período). A fim de mimetizar um estado infeccioso, LPS (2 mg/Kg: E. coli 055 B5) ou veículo (salina 0.9%) foi injetado intraperitonealmente uma vez por dia, do 25º ao 28º dia de vida. Nesse estudo, AG causou déficit de aprenizagem espacial no labirinto de Barnes, e o LPS potencializou esse prejuízo de memória induzido pelo AG nos ratos jovens. Em adição, a administração de AG e LPS aumentou os níveis de citocinas pró-inflamatórias (TNF- and IL-1), e a associação desses compostos potencializou o aumento dos níveis de IL-1, mas não de TNF-α no hipocampo dos animais. Embora a associação de AG e LPS tenha causado o aumento o conteúdo TBARS (espécies reativas ao ácido tiobarbitúrico), a redução das defesas antioxidantes e inibição da atividade da Na+,K+-ATPase (total e subunidade α1), a associação de AG e LPS não teve efeito aditivo nos marcadores de estresse oxidativo e na atividade da bomba de Na+ e K+. O volume hipocampal não foi alterado após a administração do AG e LPS. A N-acetilcisteína protegeu contra o prejuízo de aprendizagem espacial e aumento de citocinas inflamatórias induzido pelo AG e LPS. A NAC também protegeu contra os efeitos deletérios induzidos pelo AG e LPS, caracterizado pela inibição da atividade da Na+,K+-ATPase (total e subunidade α1) e aumento do conteúdo de TBARS, bem como a redução das defesas antioxidantes (tiós não-proteicos, conteúdo de glutationa, avitidade da superóxido dismutase e catalase). Esses resultados sugerem que marcadores inflamatórios e oxidativos podem estar envolvidos, em parte, na neuropatologia da AG-I neste modelo. Dessa forma, a proteção farmacológica com a NAC durante crises encefalopáticas pode ser considerada como uma terapia adjuvante para prevenir a disfunção hipocampal e a progressão da doença em crianças com AG-I.Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorapplication/pdfporUniversidade Federal de Santa MariaPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBRBioquímicaAGLPSIL-1βTNF-αMemóriaHipocampoAtividade da Na+K+-ATPaseGALPSIL-1βTNF-αMemoryHippocampusNa+,K+-ATPase activityCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAN-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovensN-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pupsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisFighera, Michele Rechiahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4762398D8Santos, Adair Roberto Soares doshttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4728656E2Fachinetto, Roseleihttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4755373E2http://lattes.cnpq.br/1048879454772088Rodrigues, Fernanda Silva2008000000024005003005005008306e5eb-747a-45a0-a023-955603a45dcd74647995-bcf5-4592-bf4b-82da2807ed37771fef6f-0577-488d-a89d-61248a73338c6a615e4f-285a-4d77-aeb6-a33cd9c07f80info:eu-repo/semantics/openAccessreponame:Repositório Institucional Manancial UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALRODRIGUES, FERNANDA SILVA.pdfapplication/pdf2366934http://repositorio.ufsm.br/bitstream/1/11227/1/RODRIGUES%2c%20FERNANDA%20SILVA.pdf0b4c3fe99a50f6d594ffd0fb62ab3a47MD51TEXTRODRIGUES, FERNANDA SILVA.pdf.txtRODRIGUES, FERNANDA SILVA.pdf.txtExtracted texttext/plain114975http://repositorio.ufsm.br/bitstream/1/11227/2/RODRIGUES%2c%20FERNANDA%20SILVA.pdf.txt3401e22bc0c4ecb2ecb2a537da920aa5MD52THUMBNAILRODRIGUES, FERNANDA SILVA.pdf.jpgRODRIGUES, FERNANDA SILVA.pdf.jpgIM Thumbnailimage/jpeg6132http://repositorio.ufsm.br/bitstream/1/11227/3/RODRIGUES%2c%20FERNANDA%20SILVA.pdf.jpg34230eff310affd19026079ff2e3d5d7MD531/112272017-07-25 12:10:42.758oai:repositorio.ufsm.br:1/11227Repositório Institucionalhttp://repositorio.ufsm.br/PUBhttp://repositorio.ufsm.br/oai/requestouvidoria@ufsm.bropendoar:39132017-07-25T15:10:42Repositório Institucional Manancial UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.por.fl_str_mv |
N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens |
dc.title.alternative.eng.fl_str_mv |
N-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pups |
title |
N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens |
spellingShingle |
N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens Rodrigues, Fernanda Silva AG LPS IL-1β TNF-α Memória Hipocampo Atividade da Na+ K+-ATPase GA LPS IL-1β TNF-α Memory Hippocampus Na+,K+-ATPase activity CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens |
title_full |
N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens |
title_fullStr |
N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens |
title_full_unstemmed |
N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens |
title_sort |
N-acetilcisteína previne a piora da memória espacial induzida por ácido glutárico e lipopolissacarídio em ratos jovens |
author |
Rodrigues, Fernanda Silva |
author_facet |
Rodrigues, Fernanda Silva |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Fighera, Michele Rechia |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4762398D8 |
dc.contributor.referee1.fl_str_mv |
Santos, Adair Roberto Soares dos |
dc.contributor.referee1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4728656E2 |
dc.contributor.referee2.fl_str_mv |
Fachinetto, Roselei |
dc.contributor.referee2Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4755373E2 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1048879454772088 |
dc.contributor.author.fl_str_mv |
Rodrigues, Fernanda Silva |
contributor_str_mv |
Fighera, Michele Rechia Santos, Adair Roberto Soares dos Fachinetto, Roselei |
dc.subject.por.fl_str_mv |
AG LPS IL-1β TNF-α Memória Hipocampo Atividade da Na+ K+-ATPase |
topic |
AG LPS IL-1β TNF-α Memória Hipocampo Atividade da Na+ K+-ATPase GA LPS IL-1β TNF-α Memory Hippocampus Na+,K+-ATPase activity CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.eng.fl_str_mv |
GA LPS IL-1β TNF-α Memory Hippocampus Na+,K+-ATPase activity |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Glutaric aciduria type I (GA-I) is an inborn error of metabolism (EIM) characterized biochemically by accumulation of glutaric acid (GA). The clinical manifestations are mainly neurological and develop during childhood. Among these changes, there are the seizures and cognitive deficits, which may be precipitated by infectious processes. Although growing evidence supports that inflammation and oxidative damage are both involved in learning impairment, it is not known whether inflammatory and oxidative stress markers facilitate GA-induced memory impairment. From this, the main objective of this study was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test on Barnes maze. To evaluate antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. Furthermore, we also evaluated wheter N-acetylcysteine (NAC) could improve these behavioral, biochemical or structural changes induced by GA and LPS administration. For this, the rat pups were injected with GA (5umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). In order to mimic a severe infection state, LPS (2 mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life.Oxidative stress biomarkers, antioxidant activity and hippocampal volume were assessed. In this study, GA caused spatial learning deficit in the Barnes maze, and that LPS potentiated the memory impairment induced by GA in rat pups. In addition, GA and LPS increased proinflammatory cytokine levels (TNF- and IL-1), and the co-administration of these compounds potentiated the increase of IL-1 levels but not TNF- levels in the hippocampus of this animals. Although GA and LPS administration increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+,K+-ATPase activity (total and subunit α1), GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. N-acetylcysteine protected against impairment of spatial learning and increase of cytokines levels induced by GA and LPS. The NAC also protected against deleterious effects induced by GA and LPS, as characterized by inhibition of Na+,K+-ATPase activity (total and subunit α1)and increase of TBARS content, as well as the reduction of antioxidant defenses(non protein thiols and glutathione content, superoxide dismutase and catalase activities).These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Pharmacological protection with NAC during encephalopatic crises could be considered as an adjuvant therapy to prevent hippocampal dysfunction and the progression of disease in children with GA-I. |
publishDate |
2014 |
dc.date.issued.fl_str_mv |
2014-03-10 |
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2015-03-04 |
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2015-03-04 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/masterThesis |
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masterThesis |
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publishedVersion |
dc.identifier.citation.fl_str_mv |
RODRIGUES, Fernanda Silva. N-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pups. 2014. 83 f. Dissertação (Mestrado em Ciências Biológicas) - Universidade Federal de Santa Maria, Santa Maria, 2014. |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/11227 |
identifier_str_mv |
RODRIGUES, Fernanda Silva. N-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pups. 2014. 83 f. Dissertação (Mestrado em Ciências Biológicas) - Universidade Federal de Santa Maria, Santa Maria, 2014. |
url |
http://repositorio.ufsm.br/handle/1/11227 |
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Universidade Federal de Santa Maria |
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UFSM |
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Bioquímica |
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Universidade Federal de Santa Maria |
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