In Vivo Cardioprotective Effects and Pharmacokinetic Profile of N-Propyl Caffeamide Against Ischemia Reperfusion Injury

Abstract

Caffeic acid derivatives constitute a class of potent anti-inflammatory and cardioprotective drug candidates. We recently synthesized a new caffeic acid derivative N-propyl caffeamide (PCA). Our pilot experiments demonstrated that PCA enhanced the survival of rat cardiomyocyte H9c2 cells against oxygen glucose deprivation and reoxygenation challenge in a concentration-dependent manner. Interestingly, PCA exhibited better cardioprotective potential than caffeic acid phenethyl ester and propyl caffeate. Thus, we hypothesized that PCA could protect heart against ischemia reperfusion (I/R) injury in mice. We first determined the stability and pharmacokinetic profile of PCA in male Sprague-Dawley rats by ultra-performance liquid chromatography coupled with UV and MS/MS detections. The stability of PCA in rat plasma was defined by the half-life of 31.39, 7.19 and 1.37 h in rat plasma at 25, 37 and 60 °C, respectively. To study the pharmacokinetic profiles, PCA was injected into male SD rats at the dose of 15 mg/kg via intravenous bolus administration. PCA showed the elimination half-life of approximate 235 min in rats. We subsequently evaluated the cardioprotective potential of PCA in mice model of myocardial infarction. Our results demonstrated that PCA effectively reduced infarct size and release of myocardial enzymes (e.g., CK, CK-MB and LDH). Biochemical analyses suggested that PCA increased the activities of antioxidant enzymes (e.g., CAT and SOD) while attenuated lipid peroxidation. Moreover, PCA profoundly reduced the number of apoptotic cells in infarcted myocardium. Consistently, PCA increased the expression level of anti-apoptotic protein Bcl2 whereas suppressed the expression of pro-apoptotic protein Bax in cardiac tissues. Collectively, PCA appears to be a novel bioavailable and stable pharmacological treatment for myocardial infarction.