Influence of GLP-1 analogue on intestinal microbiota and attenuation of doxorubicin-induced cardiotoxicity in rats

• Grant number: 22/15954-9
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2023
• End date: March 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Sergio Alberto Rupp de Paiva
• Grantee: Sergio Alberto Rupp de Paiva
• Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Doxorubicin is an effective chemotherapy used for decades in the treatment of solid and hematologic malignancies. However, its cardiotoxicity represents the most severe side effect, limiting treatment and worsening patients' quality of life. There is not a highly effective treatment to prevent cardiotoxicity. Recently, changes in gut microbiota have been related to increased risk of cardiovascular diseases and doxorubicin could induce changes in diversity and quality of microbiota. Thus, drugs that modulate gut microbiota may be a potential strategy to prevent doxorubicin-induced cardiotoxicity. GLP-1 analogs have been shown to reduce oxidative stress and inflammation and have intestinal-trophic effects. Therefore, the study aims to evaluate the role of liraglutide, a GLP-1 analog, in attenuating acute doxorubicin-induced cardiotoxicity in rats through its activity in the gut microbiota. For this, we will use 60 male Wistar rats, which will be allocated in 4 groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). The animals in groups L and DL will receive subcutaneous injection of 0.6 mg/kg liraglutide daily and groups C and D will receive saline, for 2 weeks. At the end of this period, the animals in groups D and DL will receive an intraperitoneal injection of doxorubicin 20 mg/kg once. After 48 hours of the dose of doxorubicin, the animals will be submitted to an echocardiogram, isolated heart study, and euthanasia to collect biological materials, which will be stored at -80 ° C. We will evaluate oxidative stress, heart and intestine's histology, ELISA for lipopolysaccharides, intestinal microbiota diversity and protein expression of troponin, NF-kB, TLR-2, ZO-1, Mucina-2, TNF-alpha in myocardium and colon by Western blot. Statistical analysis: 2-way ANOVA and significance adopted will be 5%. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MONTE, MARINA GAIATO; TONON, CAROLINA RODRIGUES; FUJIMORI, ANDERSON SEIJI; RIBEIRO, ANA PAULA DANTAS; ZANATI, SILMEIA GARCIA; OKOSHI, KATASHI; CAMACHO, CAMILA RENATA CORREA; MORETTO, MARIA REGINA; DE PAIVA, SERGIO ALBERTO RUPP; ZORNOFF, LEONARDO ANTONIO MAMEDE; et al. Omega-3 supplementation attenuates doxorubicin-induced cardiotoxicity but is not related to the ceramide pathway. FOOD SCIENCE & NUTRITION, v. N/A, p. 14-pg., 2024-09-29. (18/25677-7, 22/15954-9)

CABRAL, RONNY PETERSON; RIBEIRO, ANA PAULA DANTAS; MONTE, MARINA GAIATO; FUJIMORI, ANDERSON SEIJI SOARES; TONON, CAROLINA RODRIGUES; FERREIRA, NATALIA FERNANDA; ZANATTI, SILMEIA GARCIA; MINICUCCI, MARCOS FERREIRA; ZORNOFF, LEONARDO ANTONIO MAMEDE; DE PAIVA, SERGIO ALBERTO RUPP; et al. Pera orange juice (Citrus sinensis L. Osbeck) alters lipid metabolism and attenuates oxidative stress in the heart and liver of rats treated with doxorubicin. HELIYON, v. 10, n. 17, p. 11-pg., 2024-09-15. (21/09517-2, 22/15954-9)