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Edaravone mitigates hemorrhagic cystitis by modulating Nrf2, TLR?4/NF??B, and JAK1/STAT3 signaling in cyclophosphamide?intoxicated rats

Author name : EMAN KADRY MOHAMED RASHWAN
Publication Date : 2021-08-06
Journal Name : J Biochem Mol Toxicol.

Abstract

Hemorrhagic cystitis is a potentially deadly complication associated with radiation therapy
and chemotherapy. This study explored the protective effect of edaravone (ED) on cyclophosphamide
(CP)‐induced hemorrhagic cystitis, oxidative stress, and inflammation in
rats. The animals received 20mg/kg ED for 10 days and a single injection of 200mg/kg
CP on day 7. CP induced tissue injury manifested by the diffuse necrotic changes, disorganization
of lining mucosa, focal hemorrhagic patches, mucosal/submucosal inflammatory
cells infiltrates, and edema. CP increased malondialdehyde (MDA), nitric oxide
(NO), tumor necrosis factor‐alpha, and interleukin 6 (IL‐6), decreased IL‐10, and upregulated
toll‐like receptor 4 (TLR‐4), nuclear factor‐kappa B (NF‐κB) p65, Janus kinase 1
(JAK1), and signal transducer and activator of transcription 3 (STAT3) in the urinary
bladder of rats. ED effectively prevented the histopathological alterations, decreased
MDA, NO, and inflammatory mediators, and downregulated TLR‐4, NF‐κB, JAK1, and
STAT3 in CP‐induced rats. Treatment with ED upregulated ikβ kinase β, IL‐10, nuclear
factor‐erythroid 2 related factor 2 (Nrf2), and cytoglobin, and boosted glutathione, superoxide
dismutase, and glutathione S‐transferase. Molecular docking simulations revealed
the ability of ED to bind TLR‐4, NF‐κB, JAK1, and STAT3. In vitro, ED increased the
cytotoxic activity of CP against HeLa, Caco‐2, and K562 cell lines. In conclusion, ED
prevented CP‐induced hemorrhagic cystitis in rats by attenuating oxidative stress, suppressing
TLR‐4/NF‐κB, and JAK1/STAT3 signaling and boosted Nrf2, cytoglobin, and
antioxidants.

Keywords

chemotherapy, edaravone, hemorrhagic cystitis, inflammation, oxidative stress

Publication Link

https://doi.org/10.1002/jbt.22889Citations:

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