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 Ca2+, 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.