Drug Design, Development and Therapy (Nov 2020)
Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats
Abstract
Emad HM Hassanein,1 Omnia AM Abd El-Ghafar,2 Marwa A Ahmed,3 Ahmed M Sayed,4 Wail M Gad-Elrab,5 Jamaan S Ajarem,6 Ahmed A Allam,7 Ayman M Mahmoud7,8 1Department of Pharmacology and Toxicology Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt; 3Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt; 4Biochemistry Laboratory, Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt; 5Human Anatomy & Embryology Department Faculty of Medicine, Al-Azhar University, Assiut, Egypt; 6Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia; 7Zoology Department Faculty of Science, Beni-Suef University, Beni-Suef, Egypt; 8Biotechnology Department, Research Institute of Medicinal and Aromatic Plants, Beni-Suef University, Beni-Suef, EgyptCorrespondence: Ayman M MahmoudPhysiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Salah Salim Street, Beni-Suef 62514, EgyptTel +20 1278355478Email [email protected] S AjaremZoology Department, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaEmail [email protected]: 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.Materials and Methods: 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.Results: 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.Conclusion: 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.Keywords: chemotherapy, acetovanillone, edaravone, oxidative stress, cardiotoxicity, Nrf2, mTOR
