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Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-11-30 , DOI: 10.2147/dddt.s281854 Emad H M Hassanein 1 , Omnia A M 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 Mahmoud 7, 8
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-11-30 , DOI: 10.2147/dddt.s281854 Emad H M Hassanein 1 , Omnia A M 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 Mahmoud 7, 8
Affiliation
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.
Keywords: chemotherapy, acetovanillone, edaravone, oxidative stress, cardiotoxicity, Nrf2, mTOR
中文翻译：
依达拉奉和乙酰香草酮上调 Nrf2 和 PI3K/Akt/mTOR 信号传导并预防大鼠环磷酰胺心脏毒性
简介：环磷酰胺 (CP) 会导致氧化还原失衡，其使用与显着的心脏毒性有关，从而限制了其临床应用。本研究调查了乙酰香草酮 (AV) 和依达拉奉 (ED) 对 CP 诱导的氧化应激和心脏损伤的保护作用，强调了 PI3K/Akt/mTOR 和 Nrf2 信号传导的作用。
材料和方法：大鼠接受 AV (100 mg/kg) 或 ED (20 mg/kg) 口服 10 天，第 7 天接受 CP (200 mg/kg)。第 11 天处死大鼠，取样品收集分析。
结果：AV 和 ED 改善了血清肌钙蛋白 I、CK-MB、LDH、AST 和 ALP，并防止了 CP 中毒大鼠的心脏组织学改变。在 CP 诱导的大鼠中，两种治疗均降低了心脏脂质过氧化并增强了 GSH、SOD 和细胞红蛋白。AV和ED下调Keap1，而增加接受CP的大鼠心脏中PI3K、Akt、mTOR和Nrf2的表达。此外，使用分子对接模拟在计算机上确定了 AV 和 ED 与 Keap1 的结合模式。
结论： AV 和 ED 通过减轻氧化应激和组织损伤、调节细胞红蛋白、PI3K/Akt/mTOR 和 Keap1/Nrf2 信号传导来预防 CP 心脏毒性。因此，AV 和 ED 可能代表有希望的药物，可以预防接受 CP 的患者的心脏损伤。
关键词：化疗, 乙酰香草酮, 依达拉奉, 氧化应激, 心脏毒性, Nrf2, mTOR
更新日期：2020-12-01
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
中文翻译：
依达拉奉和乙酰香草酮上调 Nrf2 和 PI3K/Akt/mTOR 信号传导并预防大鼠环磷酰胺心脏毒性
简介：环磷酰胺 (CP) 会导致氧化还原失衡，其使用与显着的心脏毒性有关，从而限制了其临床应用。本研究调查了乙酰香草酮 (AV) 和依达拉奉 (ED) 对 CP 诱导的氧化应激和心脏损伤的保护作用，强调了 PI3K/Akt/mTOR 和 Nrf2 信号传导的作用。
材料和方法：大鼠接受 AV (100 mg/kg) 或 ED (20 mg/kg) 口服 10 天，第 7 天接受 CP (200 mg/kg)。第 11 天处死大鼠，取样品收集分析。
结果：AV 和 ED 改善了血清肌钙蛋白 I、CK-MB、LDH、AST 和 ALP，并防止了 CP 中毒大鼠的心脏组织学改变。在 CP 诱导的大鼠中，两种治疗均降低了心脏脂质过氧化并增强了 GSH、SOD 和细胞红蛋白。AV和ED下调Keap1，而增加接受CP的大鼠心脏中PI3K、Akt、mTOR和Nrf2的表达。此外，使用分子对接模拟在计算机上确定了 AV 和 ED 与 Keap1 的结合模式。
结论： AV 和 ED 通过减轻氧化应激和组织损伤、调节细胞红蛋白、PI3K/Akt/mTOR 和 Keap1/Nrf2 信号传导来预防 CP 心脏毒性。因此，AV 和 ED 可能代表有希望的药物，可以预防接受 CP 的患者的心脏损伤。
关键词：化疗, 乙酰香草酮, 依达拉奉, 氧化应激, 心脏毒性, Nrf2, mTOR
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