da Costa Salomão Karile Cristina, da Silva Mariana Conceição, Fabiano Lilian Catarim, de Freitas Pedro Luiz Zonta, Neves Camila Quaglio, Borges Stephanie Carvalho, Breithaupt-Faloppa Ana Cristina, Barbosa Carmem Patrícia, Buttow Nilza Cristina
Department of Morphological Sciences, State University of Maringa, Maringa, Parana, Brazil.
Department of Structural and Functional Biology, State University of Campinas, Campinas, Sao Paulo, Brazil.
Cardiovasc Toxicol. 2025 Feb;25(2):193-204. doi: 10.1007/s12012-024-09958-y. Epub 2025 Jan 26.
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.
5-氟尿嘧啶（5-FU）是一种用于治疗实体瘤的化疗药物。然而，5-FU会引发多种副作用，包括心脏毒性。鉴于心脏固有神经系统（ICNS）对心脏的重要性，且人们对5-FU对该神经丛系统的影响知之甚少，本研究旨在评估低剂量5-FU对Wistar大鼠ICNS的影响以及对心脏的氧化和炎症作用。将大鼠分为两组：对照组和5-FU组（每组n = 6）。对照组仅接受生理盐水。5-FU组接受以下临床剂量的5-FU：连续4天给予15mg/kg，随后4天给予6mg/kg并与非给药日交替，最后在第14天给予15mg/kg作为最后一剂。在第15天，将大鼠安乐死并进行开胸手术。心房用于组织学分析，心室用于生化分析。结果显示ICNS中神经元密度增加，神经节和神经元面积减小。此外，观察到组织炎症，表现为促炎因子增加以及髓过氧化物酶和N-乙酰葡糖胺酶的酶活性增加。还观察到氧化应激，这通过内源性抗氧化防御的降低和脂质过氧化的存在得到证实。5-FU治疗还导致心脏萎缩和纤维化。这些发现表明5-FU治疗存在心脏毒性，并影响ICNS的形态学方面。
