Losartan improves intestinal mucositis induced by 5-fluorouracil in mice

Maisie Mitchele Barbosa Oliveira,Conceição Da Silva Martins Rebouças,Susana Barbosa Ribeiro,Gerly Anne De Castro Brito,Aurigena Antunes De Araújo,Vitória Barros Marques,Polyana Crislayne Moreira De Sales Mota,Caroline Addison Carvalho Xavier De Medeiros,Gerlane Coelho Bernardo Guerra,Patrícia Batista Barra,Renata Ferreira De Carvalho Leitão,Jozi Godoy Figueiredo

doi:10.1038/s41598-021-01969-x

Abstract

Intestinal mucositis (IM) is a common side effect of 5-fluorouracil (5-FU)-based chemotherapy, which negatively impacts therapeutic outcomes and delays subsequent cycles of chemotherapy resulting in dose reductions and treatment discontinuation. In search of new pharmacological alternatives that minimize your symptoms, this work set out to study the effect of losartan (LOS), a receptor type I (AT1) angiotensin II antagonist, on intestinal mucositis induced by 5-FU. Intestinal mucositis was induced by a single intraperitoneal administration of 5-FU (450 mg/kg) in Swiss mice. Losartan (5, 25 or 50 mg/kg) or saline was orally administered 30 min before 5-FU and daily for 4 days. On 4th day, the animals were euthanized and segments of small intestine were collected to evaluate histopathological alterations (morphometric analysis), concentration of inflammatory cytokines, oxidative stress markers and genic expression of NF-κB p65, Fn-14 and TWEAK. Weight evaluation and changes in leukogram were also analyzed. 5-FU induced intense weight loss, leukopenia and reduction in villus height compared to saline group. Losartan (50 mg/kg) prevented 5-FU-induced inflammation by decreasing in the analyzed parameters compared to the 5-FU group. Our findings suggest that 50 mg/kg of losartan prevents the effects of 5-FU on intestinal mucosa in mice.

Highlights

Intestinal mucositis (IM) is a common side effect of 5-fluorouracil (5-FU)-based chemotherapy, which negatively impacts therapeutic outcomes and delays subsequent cycles of chemotherapy resulting in dose reductions and treatment discontinuation
All intestinal segments showed moderate to severe intestinal damage in 5-FU administered mice and losartan (50 mg/kg) significantly attenuated this injury in the jejunum and colon (Table 1)
We demonstrated that 5-FU interfered with NF-κB p65 pathway and increased gene expression of TWEAK and Fn14, compared to the saline group

Summary

Introduction

Intestinal mucositis (IM) is a common side effect of 5-fluorouracil (5-FU)-based chemotherapy, which negatively impacts therapeutic outcomes and delays subsequent cycles of chemotherapy resulting in dose reductions and treatment discontinuation. In search of new pharmacological alternatives that minimize your symptoms, this work set out to study the effect of losartan (LOS), a receptor type I (AT1) angiotensin II antagonist, on intestinal mucositis induced by 5-FU. 5-FU induced intense weight loss, leukopenia and reduction in villus height compared to saline group. Losartan (50 mg/kg) prevented 5-FU-induced inflammation by decreasing in the analyzed parameters compared to the 5-FU group. Abbreviations 5-FU 5-Fluorouracil Fn-14 Fibroblast growth factor-inducible 14 GSH Glutathione HE Hematoxylin and eosin IL-1β Interleukin 1 beta IM Intestinal mucositis LOS Losartan MDA Malondialdehyde. Post Graduate Program Pharmaceutical Science, Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil. NF-κB Nuclear transcription factor NSAIDs Non-steroidal anti-inflammatory drugs TNF-α Tumor necrosis factor alpha TWEAK Tumor necrosis factor (TNF)-like weak inducer of apoptosis

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