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Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats.

ABSTRACT: Introduction: 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.

SUBMITTER: Hassanein EHM

PROVIDER: S-EPMC7721127 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats.

Hassanein Emad H M EHM Abd El-Ghafar Omnia A M OAM Ahmed Marwa A MA Sayed Ahmed M AM Gad-Elrab Wail M WM Ajarem Jamaan S JS Allam Ahmed A AA Mahmoud Ayman M AM

Drug design, development and therapy 20201130

<h4>Introduction</h4>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.<h4>Materials and methods</h4>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 ...[more]

PMID: 33299300

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Project description:Primordial follicular depletion has thought to be a common adverse effect of chemotherapy especially for female of reproductive age. The study aimed to evaluate the protective effect of rapamycin on the primordial follicles and its potential mechanism for patients receiving chemotherapy.8-week old BALB/c female mice were randomly assigned into four groups (control; rapamycin; cyclophosphamide; and rapamycin combined with cyclophosphamide). Hematoxylin staining, immunohistochemical, TUNEL, western blotting and ELISA were employed to assess inter-group differences using Student's t-test and Mann-Whitney test.Cyclophosphamide depleted the follicular reserve and induced the phosphorylation of the key proteins of PI3K/Akt/mTOR pathway in mice in a dose-dependent manner. Co-treatment with rapamycin significantly reduced primordial follicle loss at all cyclophosphamide dose groups and prevent the follicle growth wave caused by cyclophosphamide treatment (P < 0.05). TUNEL staining showed that no apoptosis occured in the primordial follicles in all groups and fewer apoptosis in large growing follicles were observed in ovaries from rapamycin + cyclophosphamide group compared to that received cyclophosphamide alone. Serum anti-Müllerian hormone (AMH) was significantly reduced in cyclophosphamide alone group, in contrast to the normal level in rapamycin + cyclophosphamide group. Compared to p-Akt/Akt and p-mtor/mtor, p-rps6/rps6 was significantly decreased in rapamycin + cyclophosphamide group (P < 0.05), indicating that rapamycin attenuated the increased level of phosphorylation of rpS6 after cyclophosphamide treatment.Rapamycin can prevent the primordial follicle activation induced by cyclophosphamide through PI3K/Akt/mTOR signaling pathway and thus plays a role in preserving the follicle pool. These results suggest that rapamycin may be an effective protection for ovarian function during chemotherapy, which means a new nonsurgical application for protection of ovarian reserve and prevention of POF.

Dataset Information

Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats.

Publications

Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats.

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