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Published on: August 18, 2023
Acetylcholinesterase inhibition protects against trastuzumab-induced cardiotoxicity through reducing multiple
Thawatchai Khuanjing1,2,3, Chayodom Maneechote1,3, Benjamin Ongnok1,2,3
1Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Donepezil protects against Trastuzumab-induced cardiotoxicity (TIC) by reducing inflammation, oxidative stress, and cell death, thereby improving heart function. This suggests donepezil as a potential new treatment for TIC.
Area of Science:
- Cardiology
- Pharmacology
- Oncology
Background:
- Trastuzumab-induced cardiotoxicity (TIC) is a common adverse effect of cancer therapy.
- Mechanisms of TIC include oxidative stress, inflammation, and cell death, but pyroptosis and necroptosis roles are unexplored.
- Donepezil shows protective effects in heart diseases, but its efficacy in TIC is unknown.
Purpose of the Study:
- To investigate the potential cardioprotective effects of donepezil against Trastuzumab-induced cardiotoxicity in a rat model.
- To determine if donepezil mitigates mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death in TIC.
- To explore the role of muscarinic acetylcholine receptors (mAChRs) in donepezil's cardioprotective effects.
Main Methods:
- Male Wistar rats were divided into Control, Trastuzumab (Trz), and Trz + Donepezil (DPZ) groups.
- Trz was administered at 4 mg/kg/day for 7 days; DPZ was co-administered at 5 mg/kg/day.
- Cardiac function, heart rate variability (HRV), and biochemical markers were assessed. In vitro studies used a muscarinic acetylcholine receptor (mAChR) antagonist.
Main Results:
- Trastuzumab treatment impaired left ventricular (LV) function, HRV, and mitochondrial function, while increasing inflammation, oxidative stress, apoptosis, ferroptosis, and pyroptosis.
- Donepezil co-treatment significantly improved LV function and HRV, and attenuated the adverse effects of TIC.
- In vitro, donepezil's cytoprotective effects were blocked by an mAChR antagonist.
Conclusions:
- Donepezil demonstrates significant cardioprotection against Trastuzumab-induced cardiotoxicity.
- Cardioprotection is achieved by reducing mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death.
- Donepezil's effects are mediated through mAChR activation, suggesting its potential as a novel therapeutic strategy for TIC.
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