Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
Mol Med. 2023 Sep 11;29(1):123. doi: 10.1186/s10020-023-00686-7.
Trastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases. However, it remains unknown whether donepezil exerts anti-cardiotoxic effects in rats with TIC. We hypothesized that donepezil reduces mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death, leading to improved left ventricular (LV) function in rats with TIC.
Male Wistar rats were randomly assigned to be Control or Trz groups (Trz 4 mg/kg/day, 7 days, I.P.). Rats in Trz groups were assigned to be co-treated with either drinking water (Trz group) or donepezil 5 mg/kg/day (Trz + DPZ group) via oral gavage for 7 days. Cardiac function, heart rate variability (HRV), and biochemical parameters were evaluated.
Trz-treated rats had impaired LV function, HRV, mitochondrial function, and increased inflammation and oxidative stress, leading to apoptosis, ferroptosis, and pyroptosis. Donepezil co-treatment effectively decreased those adverse effects of TIC, resulting in improved LV function. An in vitro study revealed that the cytoprotective effects of donepezil were abolished by a muscarinic acetylcholine receptor (mAChR) antagonist.
Donepezil exerted cardioprotection against TIC via attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, leading to improved LV function through mAChR activation. This suggests that donepezil could be a novel intervention strategy in TIC.
曲妥珠单抗（Trz）诱导的心脏毒性（TIC）是靶向抗癌药物最常见的不良反应之一。尽管氧化应激、炎症、线粒体功能障碍、细胞凋亡和铁死亡已被确定为 TIC 的潜在机制，但 TIC 下细胞焦亡和坏死性凋亡的作用从未被研究过。已表明，使用多奈哌齐抑制乙酰胆碱酯酶功能可在各种心脏病中发挥保护作用。然而，多奈哌齐是否在 TIC 大鼠中发挥抗心脏毒性作用尚不清楚。我们假设多奈哌齐可减轻线粒体功能障碍、炎症、氧化应激和心肌细胞死亡，从而改善 TIC 大鼠的左心室（LV）功能。
雄性 Wistar 大鼠随机分为对照组或 Trz 组（Trz 4mg/kg/天，7 天，腹腔注射）。Trz 组大鼠再分为饮用水治疗组（Trz 组）或多奈哌齐 5mg/kg/天（Trz+DPZ 组）灌胃治疗 7 天。评估心脏功能、心率变异性（HRV）和生化参数。
Trz 处理的大鼠 LV 功能、HRV、线粒体功能受损，炎症和氧化应激增加，导致细胞凋亡、铁死亡和细胞焦亡。多奈哌齐联合治疗可有效减轻 TIC 的这些不良反应，从而改善 LV 功能。一项体外研究表明，多奈哌齐的细胞保护作用被毒蕈碱型乙酰胆碱受体（mAChR）拮抗剂所阻断。
多奈哌齐通过减轻线粒体功能障碍、氧化应激、炎症和心肌细胞死亡对 TIC 发挥心脏保护作用，通过 mAChR 激活改善 LV 功能。这表明多奈哌齐可能是 TIC 的一种新的干预策略。
