Cardioprotection by a Novel Necrosis Inhibitor in a Rat Model of Myocardial Ischemia-Reperfusion Injury

Abstract

Introduction: NecroX-7, a novel necrosis inhibitor, blocks the opening of mitochondrial permeability transition pore, consequently inhibits necrotic cell death which is the main pathophysiology of ischemia-reperfusion (I/R) injury. We investigated the cardioprotective effect of NecroX-7 and the minimal effective dose (MED) in vivo I/R injury model.

Methods: Rat I/R injury model was obtained by ligation of left anterior descending coronary artery for 45 minutes followed by reperfusion. 5% dextrose (vehicle) or multiple dosages of NecroX-7 (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg) was injected intravenously 5 minutes before reperfusion. Necrosis area was measured 12 hours after I/R injury, using anti-myosin antibody (n=5 per group). Echocardiograms were performed at baseline, 3rd, 7th, and 14th days, and fibrosis area was measured at 14th day (n=5 per group).

Results: Necrosis area was smaller in rats treated with 0.3 mg/kg of NecroX-7 compared to vehicle-treated group (17.0±1.2 [0.3 mg/kg of NecroX-7] versus 39.3±3.3% [vehicle], P=0.004). Dosages below 0.3 mg/kg were not effective. Left ventricular ejection fraction (LVEF) at 14th day was 57.8±1.9% in NecroX-7 group and 42.6±3.8% in vehicle group (P=0.016). LV end-systolic and end-diastolic dimensions (LVESD and LVEDD) were significantly smaller in NecroX-7 group (LVESD, 4.6±0.2 [0.3 mg/kg of NecroX-7] versus 6.4±0.4 mm [vehicle], P=0.016

LVEDD, 7.2±0.2 [0.3 mg/kg of NecroX-7] versus 8.4±0.3 mm [vehicle], P=0.008). Fibrosis area was significantly smaller in NecroX-7-treated rats when the dosages were equal or higher than 0.3 mg/kg. Serum concentrations of inflammatory cytokines confirmed the beneficial effect and the MED of NecroX-7.

Conclusions: Pretreatment with NecroX-7 reduces myocardial necrosis and preserves cardiac function and geometry in rat I/R injury model. The MED of NecroX-7 was 0.3 mg/kg. NecroX-7 is a potent candidate as a cardioprotective agent against I/R injury.