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

• Ano de defesa: 2017
• Autor(a) principal: Costa, Daniely Viana da Silva
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Palavras-chave em Português: Mucosite; Inflamação; Diarreia; Doenças Inflamatórias Intestinais
• Link de acesso: http://www.repositorio.ufc.br/handle/riufc/28523

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.