[8] and [10]-Gingerol reduces urothelial damage in ifosfamide-induced hemorrhagic cystitis via JAK/STAT/FOXO signaling pathway via IL-10

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 396; no. 8; pp. 1773 - 1786
• Main Authors: Ferreira, Francisco C. S., Clementino, Marco, Rodrigues, Francisco A. P., Veras, Herlice N., Martins, Dainesy S., Queiroga, Marcus L., Lima, Mikael A., Silva, Dayara O., de Freitas, Thiago M., Ribeiro, Samilly A., Mota, Mario R. L., da Silva, James A., Lima, Aldo A. M., Havt, Alexandre
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2023; Springer Nature B.V
• Subjects: Acrolein; Animals; Anti-inflammatory agents; Biomedical and Life Sciences; Biomedicine; Cystitis; Cystitis - chemically induced; Cystitis - drug therapy; Cystitis - pathology; Female; Forkhead protein; Gene expression; Hemorrhage; Hemorrhage - chemically induced; Hemorrhage - drug therapy; Hemorrhagic cystitis; Ifosfamide; Ifosfamide - toxicity; Inflammation; Interleukin 10; Mesna - adverse effects; Mice; Molecular modelling; Neurosciences; NF-κB protein; Oxidative stress; Peroxidase; Pharmacology/Toxicology; Signal Transduction; Mesna; Gingerol; Ifosfamide; Hemorrhagic cystitis
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-023-02436-2

Acrolein is the main toxic metabolite of ifosfamide (IFO) that causes urothelial damage by oxidative stress and inflammation. Here, we investigate the molecular mechanism of action of gingerols, Zingiber officinale bioactive molecules, as an alternative treatment for ifosfamide-induced hemorrhagic cystitis. Female Swiss mice were randomly divided into 5 groups: control; IFO; IFO + Mesna; and IFO + [8]- or [10]-gingerol. Mesna (80 mg/kg, i.p.) was given 5 min before, 4 and 8 h after IFO (400mg/kg, i.p.). Gingerols (25 mg/kg, p.o.) were given 1 h before and 4 and 8 h after IFO. Animals were euthanized 12 h after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and inflammation were assessed by malondialdehyde (MDA) or myeloperoxidase assays, respectively. mRNA gene expression was performed to evaluate mesna and gingerols mechanisms of action. Mesna was able to protect bladder tissue by activating NF-κB and NrF2 pathways. However, we demonstrated that gingerols acted as an antioxidant and anti-inflammatory agent stimulating the expression of IL-10, which intracellularly activates JAK/STAT/FOXO signaling pathway.