Donepezil exerted cardioprotection against trastuzumab-induced cardiotoxicity by attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, improving LV function.
Does donepezil improve left ventricular function and reduce cardiotoxicity in a rat model of trastuzumab-induced cardiotoxicity?
Donepezil mitigates trastuzumab-induced cardiotoxicity in rats by reducing mitochondrial dysfunction, oxidative stress, and programmed cell death pathways, suggesting a potential novel cardioprotective strategy.
p-value: p=<0.05
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.
Khuanjing et al. (2023) studied Trastuzumab-induced cardiotoxicity (n=24). Donepezil vs. Trastuzumab alone (drinking water) was evaluated on %LV ejection fraction (%LVEF) (p=<0.05). Donepezil exerted cardioprotection against trastuzumab-induced cardiotoxicity by attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, improving LV function.