Donepezil attenuated cardiac ischemia/reperfusion injury through balancing mitochondrial dynamics, mitophagy, and autophagy

Abstract

Cardiac autonomic imbalance including sympathetic overactivity and diminished parasympathetic activity is associated with left ventricular (LV) dysfunction in cases of cardiac ischemia/reperfusion (I/R) injury. Electrical stimulation to increase vagal activity has been shown to reduce infarct size and decrease fatal arrhythmias in cardiac I/R injury. However, the benefits of a parasympathomimetic drug on the heart during I/R are unclear. We hypothesized that administration of donepezil provides cardioprotection in cardiac I/R injury via reducing cellular apoptosis, oxidative stress, mitochondrial dysfunction, mitochondrial dynamic imbalance, increasing autophagy, and mitophagy. Fifty-four male Wistar rats were randomly assigned into sham and I/R groups. Acute cardiac I/R injury was induced by 30-minutes left anterior descending (LAD) coronary artery occlusion followed by 120-minutes reperfusion. These rats with induced I/R injury were randomly assigned to be treated with either: (1) Saline (vehicle group) or donepezil 3 mg/kg via intravenous injection given (2) before ischemia, (3) during ischemia, or (4) at the onset of reperfusion. Rats with cardiac I/R injury showed an increase in infarct size and arrhythmia score, LV dysfunction, impaired mitochondrial dynamic balance, autophagy and mitophagy, mitochondrial dysfunction, and increased apoptosis. All the donepezil-treated rats, regardless of the time of administration, showed a similar reduction in these impairments, and rebalancing in cardiac mitochondrial dynamics, leading to reduced myocardial infarct size and arrhythmia, and improved LV function. These findings suggested that donepezil effectively protected the heart against I/R injury through cardiac mitochondrial protection regardless of the time of administration.