Discovery of β‑Carboline Derivatives as a Highly Potent Cardioprotectant against Myocardial Ischemia-Reperfusion Injury

Timely myocardial reperfusion salvages
ischemic myocardium from
infarction, whereas reperfusion itself induces cardiomyocyte death,
which is called myocardial ischemia/reperfusion (MI/R) injury. Herein,
β-carboline derivative 17c was designed and synthesized
with obvious myocardial protective activity for the first time. Pretreatment
of 17c effectively protected the cardiomyocyte H9c2 cells
from H2O2-induced lactate dehydrogenase leakage
and restored the endogenous antioxidants, superoxide dismutase (SOD)
and glutathione peroxidase (GSH-Px). Besides, 17c effectively
protected the mitochondria through decreasing the reactive oxygen
species overproduction and enhancing the mitochondrial membrane potential.
As a result, 17c significantly reduced the necrosis of
cardiomyocytes in H2O2-induced oxidative stress,
which was more potent than polydatin. In MI/R injury rats, 17c pretreatment obviously increased the levels of SOD and GSH-Px and
inhibited the apoptosis of cardiomyocytes. Through this way, the size
of myocardial infarction was significantly reduced after MI/R injury in vivo, better than that of polydatin, suggesting that 17c is a promising cardioprotectant for the prevention of
MI/R injury.