Agomelatine Protects Against Myocardial Ischemia Reperfusion Injury by Inhibiting Mitochondrial Permeability Transition Pore Opening

Agomelatine is a melatonin (MT1/MT2) receptor agonist and serotonin (5-HT2C) receptor antagonist. To study the effects of agomelatine on myocardial ischemia reperfusion injury (MIRI), an isolated rat heart model was utilized. To induce MIRI, rat hearts were isolated and subjected to 30 min of ischemia followed by 120 min of reperfusion. Rats were intraperitoneally injected with agomelatine (10, 20 or 40 mg/kg) 1 h before heart isolation. Agomelatine (20 mg/kg and 40 mg/kg) significantly improved cardiac function, alleviated pathological changes in the ischemic myocardium, reduced myocardial infarct size and decreased release of creatine kinase-MB and lactate dehydrogenase. Heart tissue from agomelatine-treated rats retained higher NAD content and was more resistant to Ca, indicating inhibition of mitochondrial permeability transition pore (MPTP) opening. Notably, agomelatine's protective effects were abrogated by atractyloside, a MPTP opener. We also found that agomelatine significantly enhanced GSK-3β phosphorylation and decreased expression of cytochrome C, cleaved caspase 9 and cleaved caspase 3, resulting in a decreased apoptosis rate. These findings demonstrate that agomelatine protects against MIRI by inhibiting MPTP opening.