Acetylcholinesterase inhibitor ameliorates doxorubicin-induced cardiotoxicity through reducing RIP1-mediated necroptosis

心脏毒性 粒体自噬 药理学 坏死性下垂 心肌保护 自噬 阿霉素 细胞凋亡 氧化应激 程序性细胞死亡 活性氧 线粒体 医学 生物 内科学 细胞生物学 生物化学 缺血 化疗
作者
Thawatchai Khuanjing,Benjamin Ongnok,Chayodom Maneechote,Natthaphat Siri‐Angkul,Nanthip Prathumsap,Apiwan Arinno,Titikorn Chunchai,Busarin Arunsak,Nipon Chattipakorn,Nipon Chattipakorn
出处
期刊:Pharmacological Research [Elsevier]
卷期号:173: 105882-105882 被引量:33
标识
DOI:10.1016/j.phrs.2021.105882
摘要

Doxorubicin is an effective chemotherapeutic drug, but causes cardiotoxicity which limits its use. Oxidative stress, mitochondrial dysfunction, and inflammation are closely implicated in doxorubicin-induced cardiotoxicity (DIC). Necroptosis, a new form of programmed cell death, was also upregulated by doxorubicin, leading to cardiomyocyte death and cardiac dysfunction. Donepezil, an acetylcholinesterase inhibitor, exerted cardioprotection against various heart diseases. However, its cardioprotective effects in DIC are still unknown. We hypothesized that donepezil reduces reactive oxygen species (ROS) production, mitochondrial dysfunction, mitochondrial dynamics imbalance, necroptosis, and apoptosis in DIC rats. Male Wistar rats were assigned to receive either normal saline solution (n = 8) or doxorubicin (3 mg/kg, 6 doses, n = 16) via intraperitoneal injection. The doxorubicin-treated rats were further subdivided to receive either sterile drinking water (n = 8) or donepezil (5 mg/kg/day, p.o., n = 8) for 30 days. At the end of the experiment, the left ventricular (LV) function was determined. Serum and heart tissue were collected to evaluate histological and biochemical parameters. Doxorubicin-treated rats exhibited higher levels of inflammatory cytokines and ROS production. Doxorubicin also impaired mitochondrial function, mitochondrial dynamics balance, mitophagy, and autophagy, which culminated in apoptosis. Furthermore, doxorubicin increased necroptosis as evidenced by increased phosphorylation of receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed-lineage kinase domain-like. All of these mechanisms led to LV dysfunction. Interestingly, donepezil alleviated mitochondrial injury, mitophagy, autophagy, and cardiomyocyte death, leading to improved LV function in DIC. In conclusion, donepezil attenuated DIC-induced LV dysfunction by reducing mitochondrial damage, mitophagy, autophagy, apoptosis, and necroptosis.
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