O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano

Detalhes bibliográficos
Autor(a) principal: Costa, Daniely Viana da Silva
Data de Publicação: 2017
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Repositório Institucional da Universidade Federal do Ceará (UFC)
Texto Completo: http://www.repositorio.ufc.br/handle/riufc/28523
Resumo: Irinotecan is widely used in the treatment of colorectal cancer. However, it promotes intestinal mucositis and changes on intestine motility. Mucositis affects approximately 40% of patients receiving irinotecan and there are reports of patients presenting with the first dose administered. In addition, late diarrhea is one of the major problems presented by patients using this chemotherapy. In this context, several studies have investigated the effect of several substances on the prevention of irinotecan-induced mucositis and diarrhea, but there is no evidence of alpha-lipoic acid (ALA) studies in this area. ALA has showed an important effect on the prevention of alterations in motility induced by experimental colitis and has an important effect on the modulation of the neuroinflammation in several experimental models, such as depression. Thus, the objective of this study was to investigate the effect of ALA on experimental intestinal mucositis by irinotecan. This study was approved by the animal research ethics committee of the Federal University of Ceará (protocol nº. 31/2016). Male Swiss mice (25 to 30 g) received saline (0.9%, i.p.) or irinotecan (75 mg/kg, i.p.) once daily for four days. However, ALA (50, 100 or 200 mg / kg, gavage) was injected one hour prior of the irinotecan or saline. The animals were euthanized by decapitation on the fifth or seventh day of the experimental protocol. On the fifth day, segments of the small intestine (duodenum, jejunum and ileum) were removed for analysis of histopathological changes, levels of MPO, GSH and proinflammatory cytokines (IL-6 and TNF-α), including expression of IL-1β and Ki67 by immunohistochemistry. On the seventh day, the diarrhea score, the gastric emptying, the intestinal transit and changes in the length of the small intestine (as an indirect measure of intestinal hypercontractility) were evaluated. In addition, the animals were monitored daily for body mass and survival analysis. Irinotecan decreased the height of intestinal villi, caused loss of intestinal crypt architecture and induced formation of intense inflammatory cell infiltration into segments of the small intestine (duodenum, jejunum, and ileum). In addition, it reduced (P<0.05) Ki67 expression in intestinal crypts, increased (P<0.05) MPO, IL-6 and TNF-α levels and decreased (P<0.05) GSH levels in duodenum segments. Irinotecan also increased (P<0.0001) retention of the test meal (phenol red) in the stomach and decreased it (P <0.0001) in the medial segment of the small intestine, indicating delayed gastric emptying and increased intestinal transit respectively. In addition, irinotecan reduced the body mass and survival of the animals submitted to intestinal mucositis induced by irinotecan compared to control group. The pretreatment with ALA (200 mg/kg) prevented these irinotecan-induced changes in the duodenum. In addition, ALA decreased diarrhea and changes in intestinal motility and increased survival of animals undergoing the irinotecaninduced intestinal mucositis. ALA reduces the inflammation, intestinal dysmotility and diarrhea induced by irinotecan, as well as improves the survival of the animals treated with this chemotherapeutic. ALA may be an important therapeutic agent to prevent intestinal dysmotility in patients receiving irinotecan.
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spelling O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecanoThe effect of alpha-lipoic acid on experimental intestinal mucositis by irinotecanMucositeInflamaçãoDiarreiaDoenças Inflamatórias IntestinaisIrinotecan is widely used in the treatment of colorectal cancer. However, it promotes intestinal mucositis and changes on intestine motility. Mucositis affects approximately 40% of patients receiving irinotecan and there are reports of patients presenting with the first dose administered. In addition, late diarrhea is one of the major problems presented by patients using this chemotherapy. In this context, several studies have investigated the effect of several substances on the prevention of irinotecan-induced mucositis and diarrhea, but there is no evidence of alpha-lipoic acid (ALA) studies in this area. ALA has showed an important effect on the prevention of alterations in motility induced by experimental colitis and has an important effect on the modulation of the neuroinflammation in several experimental models, such as depression. Thus, the objective of this study was to investigate the effect of ALA on experimental intestinal mucositis by irinotecan. This study was approved by the animal research ethics committee of the Federal University of Ceará (protocol nº. 31/2016). Male Swiss mice (25 to 30 g) received saline (0.9%, i.p.) or irinotecan (75 mg/kg, i.p.) once daily for four days. However, ALA (50, 100 or 200 mg / kg, gavage) was injected one hour prior of the irinotecan or saline. The animals were euthanized by decapitation on the fifth or seventh day of the experimental protocol. On the fifth day, segments of the small intestine (duodenum, jejunum and ileum) were removed for analysis of histopathological changes, levels of MPO, GSH and proinflammatory cytokines (IL-6 and TNF-α), including expression of IL-1β and Ki67 by immunohistochemistry. On the seventh day, the diarrhea score, the gastric emptying, the intestinal transit and changes in the length of the small intestine (as an indirect measure of intestinal hypercontractility) were evaluated. In addition, the animals were monitored daily for body mass and survival analysis. Irinotecan decreased the height of intestinal villi, caused loss of intestinal crypt architecture and induced formation of intense inflammatory cell infiltration into segments of the small intestine (duodenum, jejunum, and ileum). In addition, it reduced (P<0.05) Ki67 expression in intestinal crypts, increased (P<0.05) MPO, IL-6 and TNF-α levels and decreased (P<0.05) GSH levels in duodenum segments. Irinotecan also increased (P<0.0001) retention of the test meal (phenol red) in the stomach and decreased it (P <0.0001) in the medial segment of the small intestine, indicating delayed gastric emptying and increased intestinal transit respectively. In addition, irinotecan reduced the body mass and survival of the animals submitted to intestinal mucositis induced by irinotecan compared to control group. The pretreatment with ALA (200 mg/kg) prevented these irinotecan-induced changes in the duodenum. In addition, ALA decreased diarrhea and changes in intestinal motility and increased survival of animals undergoing the irinotecaninduced intestinal mucositis. ALA reduces the inflammation, intestinal dysmotility and diarrhea induced by irinotecan, as well as improves the survival of the animals treated with this chemotherapeutic. ALA may be an important therapeutic agent to prevent intestinal dysmotility in patients receiving irinotecan.O irinotecano é largamente usado no tratamento de câncer colorretal. No entanto, promove mucosite intestinal e alterações da motilidade. A mucosite atinge cerca de 40% dos pacientes em tratamento com irinotecano e há relatos de pacientes que a apresentam na primeira dose administrada. Em adição, a diarreia tardia é um dos grandes problemas enfrentados pelos pacientes em uso desse quimioterápico. Nesse contexto, diversos estudos vêm explorando o efeito de diversas substâncias na prevenção da mucosite e da diarreia induzidas por irinotecano, porém não há evidências de pesquisas com ácido alfa-lipóico (ALA) nessa área. O ALA tem demonstrado importante efeito na prevenção de alterações da motilidade induzida pela colite experimental, além de ter importante efeito na modulação da neuroinflamação em diversos modelos experimentais como a depressão. Dessa forma, o objetivo deste estudo foi investigar o efeito do ALA na mucosite intestinal experimental por irinotecano. Este estudo foi aprovado pelo comitê de ética em pesquisa animal da Universidade Federal do Ceará sob o protocolo de n° 31/2016. Camundongos Swiss machos (25 a 30 g) receberam salina (0,9%, i.p.) ou irinotecano (75 mg/kg, i.p.) uma vez ao dia durante quatro dias. No entanto, uma hora antes injetou-se ALA (50, 100 ou 200 mg/kg, gavagem). Os animais foram eutanasiados por decapitação no quinto ou no sétimo dia do protocolo experimental. No quinto dia, os segmentos do intestino delgado (duodeno, jejuno e íleo) foram removidos para análise da atividade da acetilcolinesterase, das alterações histopatológica, dos níveis de MPO, GSH e citocinas pró-inflamatórias (IL-6 e TNF-α), incluindo da expressão de IL-1β e de Ki67 por imunohistoquímica. No sétimo dia, avaliaram-se o escore de diarreia, o esvaziamento gástrico, o trânsito intestinal e alterações do comprimento do intestino delgado. Além disso, os animais foram acompanhados diariamente para análise da massa corporal e da sobrevida. Irinotecano diminuiu a altura das vilosidades intestinais, causou perda da arquitetura das criptas intestinais e formação de intenso infiltrado de células inflamatórias em segmentos do intestino delgado (duodeno, jejuno e íleo). Além disso, reduziu (p<0,05) a expressão de Ki67 nas criptas intestinais, aumentou (P<0,05) os níveis de MPO, IL-6 e TNF-α e diminuiu (P<0,05) o de GSH em segmentos do duodeno. Irinotecano também aumentou (P<0.0001) a retenção da refeição teste (vermelho de fenol) no estômago e a diminuiu (P<0.0001) no segmento medial do intestino delgado, indicando retardo do esvaziamento gástrico e aumento do trânsito intestinal respectivamente. Em adição, irinotecano diminuiu a massa corporea e a sobrevida dos animais submetidos à mucosite intestinal experimental comparado ao grupo controle. Enquanto que o pré-tratamento com ALA (200 mg/kg) foi capaz de prevenir essas alterações induzidas por irinotecano no duodeno. Além disso, ALA diminuiu a diarreia e as alterações na motilidade intestinal e aumentou a sobrevida de animais submetidos à mucosite intestinal induzida por irinotecano. Constatou-se que irinotecano diminuiu a atividade da acetilcolinesterase apenas no jejuno. Ao passo que ALA não reverteu esse efeito em nenhum dos segmentos avaliados. Com base nos resultados, ALA reduz a inflamação, a dismotilidade intestinal e a diarreia induzidas por irinotecano, bem como melhora a sobrevida dos animais tratados com esse quimioterápico. ALA pode ser um importante agente terapêutico para prevenir a dismotilidade intestinal em pacientes sob tratamento com irinotecano.Souza, Emmanuel Prata deCosta, Daniely Viana da Silva2017-12-18T11:04:30Z2017-12-18T11:04:30Z2017-01-31info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfCOSTA, D. V. S. O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano. 2017. 82 f. Dissertação (Mestrado em Ciências Morfofuncionais) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2017.http://www.repositorio.ufc.br/handle/riufc/28523porreponame:Repositório Institucional da Universidade Federal do Ceará (UFC)instname:Universidade Federal do Ceará (UFC)instacron:UFCinfo:eu-repo/semantics/openAccess2018-12-13T17:39:10Zoai:repositorio.ufc.br:riufc/28523Repositório InstitucionalPUBhttp://www.repositorio.ufc.br/ri-oai/requestbu@ufc.br || repositorio@ufc.bropendoar:2024-09-11T18:55:28.097875Repositório Institucional da Universidade Federal do Ceará (UFC) - Universidade Federal do Ceará (UFC)false
dc.title.none.fl_str_mv O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano
The effect of alpha-lipoic acid on experimental intestinal mucositis by irinotecan
title O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano
spellingShingle O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano
Costa, Daniely Viana da Silva
Mucosite
Inflamação
Diarreia
Doenças Inflamatórias Intestinais
title_short O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano
title_full O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano
title_fullStr O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano
title_full_unstemmed O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano
title_sort O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano
author Costa, Daniely Viana da Silva
author_facet Costa, Daniely Viana da Silva
author_role author
dc.contributor.none.fl_str_mv Souza, Emmanuel Prata de
dc.contributor.author.fl_str_mv Costa, Daniely Viana da Silva
dc.subject.por.fl_str_mv Mucosite
Inflamação
Diarreia
Doenças Inflamatórias Intestinais
topic Mucosite
Inflamação
Diarreia
Doenças Inflamatórias Intestinais
description Irinotecan is widely used in the treatment of colorectal cancer. However, it promotes intestinal mucositis and changes on intestine motility. Mucositis affects approximately 40% of patients receiving irinotecan and there are reports of patients presenting with the first dose administered. In addition, late diarrhea is one of the major problems presented by patients using this chemotherapy. In this context, several studies have investigated the effect of several substances on the prevention of irinotecan-induced mucositis and diarrhea, but there is no evidence of alpha-lipoic acid (ALA) studies in this area. ALA has showed an important effect on the prevention of alterations in motility induced by experimental colitis and has an important effect on the modulation of the neuroinflammation in several experimental models, such as depression. Thus, the objective of this study was to investigate the effect of ALA on experimental intestinal mucositis by irinotecan. This study was approved by the animal research ethics committee of the Federal University of Ceará (protocol nº. 31/2016). Male Swiss mice (25 to 30 g) received saline (0.9%, i.p.) or irinotecan (75 mg/kg, i.p.) once daily for four days. However, ALA (50, 100 or 200 mg / kg, gavage) was injected one hour prior of the irinotecan or saline. The animals were euthanized by decapitation on the fifth or seventh day of the experimental protocol. On the fifth day, segments of the small intestine (duodenum, jejunum and ileum) were removed for analysis of histopathological changes, levels of MPO, GSH and proinflammatory cytokines (IL-6 and TNF-α), including expression of IL-1β and Ki67 by immunohistochemistry. On the seventh day, the diarrhea score, the gastric emptying, the intestinal transit and changes in the length of the small intestine (as an indirect measure of intestinal hypercontractility) were evaluated. In addition, the animals were monitored daily for body mass and survival analysis. Irinotecan decreased the height of intestinal villi, caused loss of intestinal crypt architecture and induced formation of intense inflammatory cell infiltration into segments of the small intestine (duodenum, jejunum, and ileum). In addition, it reduced (P<0.05) Ki67 expression in intestinal crypts, increased (P<0.05) MPO, IL-6 and TNF-α levels and decreased (P<0.05) GSH levels in duodenum segments. Irinotecan also increased (P<0.0001) retention of the test meal (phenol red) in the stomach and decreased it (P <0.0001) in the medial segment of the small intestine, indicating delayed gastric emptying and increased intestinal transit respectively. In addition, irinotecan reduced the body mass and survival of the animals submitted to intestinal mucositis induced by irinotecan compared to control group. The pretreatment with ALA (200 mg/kg) prevented these irinotecan-induced changes in the duodenum. In addition, ALA decreased diarrhea and changes in intestinal motility and increased survival of animals undergoing the irinotecaninduced intestinal mucositis. ALA reduces the inflammation, intestinal dysmotility and diarrhea induced by irinotecan, as well as improves the survival of the animals treated with this chemotherapeutic. ALA may be an important therapeutic agent to prevent intestinal dysmotility in patients receiving irinotecan.
publishDate 2017
dc.date.none.fl_str_mv 2017-12-18T11:04:30Z
2017-12-18T11:04:30Z
2017-01-31
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv COSTA, D. V. S. O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano. 2017. 82 f. Dissertação (Mestrado em Ciências Morfofuncionais) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2017.
http://www.repositorio.ufc.br/handle/riufc/28523
identifier_str_mv COSTA, D. V. S. O efeito do ácido alfa-lipóico na mucosite intestinal experimental por irinotecano. 2017. 82 f. Dissertação (Mestrado em Ciências Morfofuncionais) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2017.
url http://www.repositorio.ufc.br/handle/riufc/28523
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