Cardiotoxicity Associated With a Low Doses of 5-FU Promotes Morphoquantitative Changes in the Intrinsic Cardiac Nervous System

Abstract

5-Fluorouracil (5-FU) is a chemotherapeutic that is used to treat solid tumors. However, 5-FU is associated with several side effects, including cardiotoxicity. Considering the importance of the intrinsic cardiac nervous system (ICNS) for the heart and that little is known about effects of 5-FU on this nervous system plexus, the purpose of the present study was to evaluate effects 5-FU at a low dose on the ICNS and oxidative and inflammatory effects in the heart in Wistar rats. The rats were divided into two groups: treated and 5-FU (n = 6/group). The control group received saline only. The treated group received the following clinical doses of 5-FU: 15 mg/kg for 4 consecutive days, followed by 6 mg/kg for 4 days alternated with non-treatment days, and finally 15 mg/kg as the last dose on day 14. On day 15, the rats were euthanized and underwent thoracotomy. The atria were used for histological analysis, and the ventricles were used for biochemical analysis. The results showed an increase in neuronal density and a decrease in ganglionic and neuronal area in the ICNS. Furthermore, tissue inflammation was observed, indicated by an increase in proinflammatory factors and the enzymatic activity of myeloperoxidase and n-acetyl-glucosaminidase. Oxidative stress was also observed, confirmed by a reduction of endogenous antioxidant defenses and the presence of lipoperoxidation. Treatment with 5-FU also caused cardiac atrophy and fibrosis. These findings indicate that cardiotoxicity is present with 5-FU treatment and affects the morphometric aspects of the ICNS.

Keywords: Cardiac plexus; Fibrosis; Heart; Inflammation; Neurons; Oxidative stress.