Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats.
Acetophenones
/ administration & dosage
Administration, Oral
Animals
Antioxidants
/ administration & dosage
Cyclophosphamide
Edaravone
/ administration & dosage
Male
Molecular Docking Simulation
Myocardial Reperfusion Injury
/ chemically induced
NF-E2-Related Factor 2
/ metabolism
Phosphatidylinositol 3-Kinase
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Rats
Rats, Wistar
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ metabolism
Up-Regulation
/ drug effects
Nrf2
acetovanillone
cardiotoxicity
chemotherapy
edaravone
mTOR
oxidative stress
Journal
Drug design, development and therapy
ISSN: 1177-8881
Titre abrégé: Drug Des Devel Ther
Pays: New Zealand
ID NLM: 101475745
Informations de publication
Date de publication:
2020
2020
Historique:
received:
17
09
2020
accepted:
11
11
2020
entrez:
10
12
2020
pubmed:
11
12
2020
medline:
22
9
2021
Statut:
epublish
Résumé
Cyclophosphamide (CP) causes redox imbalance and its use is associated with marked cardiotoxicity that limits its clinical applications. The present study investigated the protective effects of acetovanillone (AV) and edaravone (ED) against CP-induced oxidative stress and cardiac damage, emphasizing the role of PI3K/Akt/mTOR and Nrf2 signaling. Rats received either AV (100 mg/kg) or ED (20 mg/kg) orally for 10 days and CP (200 mg/kg) on day 7. At day 11, the rats were sacrificed, and samples were collected for analysis. AV and ED ameliorated serum troponin I, CK-MB, LDH, AST and ALP, and prevented cardiac histological alterations in CP-intoxicated rats. Both treatments decreased cardiac lipid peroxidation and enhanced GSH, SOD and cytoglobin in CP-induced rats. AV and ED downregulated Keap1, whereas increased the expression of PI3K, Akt, mTOR and Nrf2 in the heart of rats received CP. Additionally, the binding modes of AV and ED to Keap1 were pinpointed in silico using molecular docking simulations. AV and ED prevent CP cardiotoxicity by attenuating oxidative stress and tissue injury, and modulating cytoglobin, and PI3K/Akt/mTOR and Keap1/Nrf2 signaling. Therefore, AV and ED may represent promising agents that can prevent cardiac injury in patients receiving CP.
Identifiants
pubmed: 33299300
doi: 10.2147/DDDT.S281854
pii: 281854
pmc: PMC7721127
doi:
Substances chimiques
Acetophenones
0
Antioxidants
0
NF-E2-Related Factor 2
0
Nfe2l2 protein, rat
0
Cyclophosphamide
8N3DW7272P
acetovanillone
B6J7B9UDTR
mTOR protein, rat
EC 2.7.1.1
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Edaravone
S798V6YJRP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5275-5288Informations de copyright
© 2020 Hassanein et al.
Déclaration de conflit d'intérêts
The authors declare that there are no potential conflicts of interest.
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