Treinamento intervalado de alta intensidade melhora o status redox hepático via ativação da sinalização de Nrf2 e redução da expressão de CYP2E1 em ratas com hepatotoxicidade induzida por cisplatina

Abstract

Cisplatin (CP) is a widely used chemotherapeutic agent for the treatment of various types of cancer, but its use is limited by several cytotoxic adverse effects, including hepatotoxicity. Oxidative stress is a key mechanism in CP-induced liver damage, primarily mediated by increased production of reactive oxygen species (ROS) and the upregulation of CYP2E1. Physical training can improve redox status, thereby offering hepatoprotection. This study compared the effects of low-intensity continuous training (LICT), moderate-intensity continuous training (MICT), and high-intensity interval training (HIIT) on CP-induced hepatotoxicity in Wistar rats. The rats were divided into five groups (n = 7): sedentary control (C+S), cisplatin and sedentary (CP+S), cisplatin and subjected to LICT (CP+LICT), cisplatin and subjected to MICT (CP+MICT), and cisplatin and subjected to HIIT (CP+HIIT). The training protocols consisted of eight weeks of treadmill running performed prior to CP administration (5 mg/kg; intraperitoneal). Seven days after the CP injection, the animals were euthanized for analysis of serum biochemical parameters (albumin, bilirubin, AST, and ALT), histopathological assessments, enzyme-linked immunosorbent assays, immunohistochemistry, and gene expression analysis via real-time PCR. These evaluations assessed oxidative and nitrosative damage, antioxidant status, and the expression of CYP2E1 and Nrf2 proteins. Statistical analyses were performed using a one-way ANOVA, followed by Newman-Keuls multiple comparison test, with the GraphPad Prism 5 software. Statistical significance was set at p < 0.05. The results demonstrate that only the CP+S group exhibited an increase in bilirubin levels and a reduction in ALT levels, while all three training protocols effectively prevented these effects. Among them, HIIT was the most effective protocol in preventing histopathological alterations and reducing markers of oxidative and nitrosative damage to cellular macromolecules, including 4-HNE (lipids), nitrotyrosine (proteins), and 8-OHdG (DNA) induced by CP. The reduction in these markers appears to be associated with decreased CYP2E1 levels. Furthermore, HIIT activated the Nrf2 signaling pathway and increased the expression of downstream antioxidant enzymes, such as SOD1, catalase, GPx, and HO-1. In conclusion, HIIT emerged as the most effective protocol for mitigating liver damage, possibly through CYP2E1 suppression and enhanced antioxidant defenses via Nrf2 signaling pathway activation.