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Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5-fluorouracil

AutorMcQuade, Rachel M.; Stojanovska, Vanesa; Abalo, Raquel; Bornstein, Joel C.; Nurgali, Kulmira
Palabras clave5-FU
Myenteric neurons
Gastrointestinal transit
Enteric neuropathy
Colonic motility
Fecha de publicación2016
CitaciónNeurogastroenterology and Motility 28(12): 1861-1875 (2016)
Resumen[Background]: The use of the anticancer chemotherapeutic agent 5-fluorouracil (5-FU) is often limited by nausea, vomiting, constipation, and diarrhea; these side-effects persist long after treatment. The effects of 5-FU on enteric neurons have not been studied and may provide insight into the mechanisms underlying 5-FU-induced gastrointestinal dysfunction. [Methods]: Balb/c mice received intraperitoneal injections of 5-FU (23 mg/kg) 3 times/week for 14 days. Gastrointestinal transit was analysed in vivo prior to and following 3, 7, and 14 days of 5-FU treatment via serial x-ray imaging. Following 14 days of 5-FU administration, colons were collected for assessment of ex vivo colonic motility, gross morphological structure, and immunohistochemical analysis of myenteric neurons. Fecal lipocalin-2 and CD45 leukocytes in the colon were analysed as markers of intestinal inflammation. [Key Results]: Short-term administration of 5-FU (3 days) increased gastrointestinal transit, induced acute intestinal inflammation and reduced the proportion of neuronal nitric oxide synthase-immunoreactive neurons. Long-term treatment (7, 14 days) resulted in delayed gastrointestinal transit, inhibition of colonic migrating motor complexes, increased short and fragmented contractions, myenteric neuronal loss and a reduction in the number of ChAT-immunoreactive neurons after the inflammation was resolved. Gross morphological damage to the colon was observed following both short- and long-term 5-FU treatment. [Conclusions & Inferences]: Our results indicate that 5-FU induces accelerated gastrointestinal transit associated with acute intestinal inflammation at day 3 after the start of treatment, which may have led to persistent changes in the ENS observed after days 7 and 14 of treatment contributing to delayed gastrointestinal transit and colonic dysmotility.
Versión del editorhttps://doi.org/10.1111/nmo.12890
Identificadoresdoi: 10.1111/nmo.12890
e-issn: 1365-2982
issn: 1350-1925
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