Effects of a novel inhibitor of lipid peroxidation on injury caused by oxidative stress and ischemia-reperfusion

Dr. Nagy András
Effects of a novel inhibitor of lipid peroxidation on injury caused by oxidative stress and ischemia-reperfusion.
Doktori értekezés, Szegedi Tudományegyetem.

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Introduction. Coronary artery disease with an eventual coronary occlusion and subsequent myocardial injury is one of the leading causes of death in the world. Besides spontaneous reperfusion of an occluded artery thrombolysis and percutaneous transluminal coronary angioplasty (PTCA)are two procedures performed widely, that aim for the restoration of blood flow, i.e. also result in reperfusion. Reperfusion may increase injury over and above that sustained during ischemia. One of the suggested mechanisms of so-called reperfusion injury is the generation and action of reactive oxygen species (ROS). Although in clinical conditions timely reperfusion of the ischemic area is the cornerstone of treatment, there is a possible role of antioxidant therapy to limit ischemia-reperfusion injury. Aims. I. To investigate the protective efficacy of H290/51, a low molecular weight, hydrophilic compound with effects similar to Vitamin E and inhibiting lipid peroxidation, on hypoxia-reoxygenation injury of isolated cardiomyocytes. II. To study the effect of H290/51 on oxidative injury induced by exogenous ROS in isolated, perfused rat hearts. III. To examine its effect on ultrastructural changes in isolated rat hearts subjected to ischemia and reperfusion. IV. To assess the effect of inhibiting lipid peroxidation on functional and biochemical injury caused by global, normothermic ischemia-reperfusion in isolated rat hearts. Methods. I. Neonatal myocytes were cultured. On day 6 cells were rendered hypoxic for 1 hour followed by 4 hours of reoxygenation. Lactate dehydrogenase (LDH) leakage was assessed. II. Oxidative injury was induced in isolated rat hearts by perfusion with H2O2 for 10 min, followed by 50 minutes of recovery. Functional (heart rate [HR], coronary flow [CF], left ventricular end-diastolic pressure [LVEDP], left ventricular developed pressure [LVDP]) and biochemical ([LDH leakage], thiobarbituric acid parameters were measured. III. Isolated rat hearts were subjected to 30 minutes of global, normothermic ischemia, followed by 20 minutes of reperfusion. Hearts were sampled for electron microscopy. Quantitative stereological morphometry was employed. IV. Isolated rat hearts were subjected to 30 minutes of global, normothermic ischemia, followed by reperfusion for 20 minutes. Functional (HR, CF, LVDP, LVEDP) and biochemical (LDH leakage, TBARS) parameters were measured. Materials. A novel low molecular weight indenoindole derivative, H290/51 (cis-5, 5a, 6,10,b-tetrahydro-9-methoxy-7-methylindeno [2,1-b]indole) was selected as the antioxidant in the experiments. The compound is an inhibitor of lipid peroxidation, with balanced hydro- and lipophilicity, thus it can rapidly penetrate cell membranes to intracellular sites of ROS generation, lipid peroxidation and oxidant injury. Results. I. H290/51 inhibited LDH leakage in isolated cardiomyocytes induced by hypoxia-reoxygenation in a dose-dependent manner. II. H290/51 attenuated diastolic dysfunction as it inhibited the increase in LVEDP caused by H2O2. The protective effect was further evidenced by the inhibition of both LDH release and accumulation of TBARS after H2O2 exposure. III. Ischemia-induced increase in interstitial volume and in volume fractions of myocytes and interstitium was inhibited by H290/51. The difference was already present at the end of ischemia, but disappeared during reperfusion. IV. Ischemia caused an increase in LVEDP and decrease in LVDP and CF, and induced malignant arrhythmias. H290/51 effectively inhibited these changes if it was administered throughout the experiment including the stabilization period before ischemia, but was less potent when given only during reperfusion. Conclusion. Our study indicates that inhibiting lipid peroxidation by H290/51 counteracts several deleterious processes in an experimental myocardial ischemia/reperfusion injury model. Our data indicate that to some extent its antioxidant properties may be effective not only during reperfusion, but already during ischemia. Thus, a better preserved functional and morphological status of the myocardium during ischemia may yield a better capacity to survive reperfusion injury. The chemical properties of the compound, most importantly its balanced hydro- and lipophilicity and its small molecular weight result in its ability to rapidly reach the intracellular sites where induced free radicals are produced. Clinically, such properties might be of therapeutic value, and H290/51 may therefore be a promising candidate for clinical evaluation and further study.

Mű típusa: Disszertáció (Doktori értekezés)
Doktori iskola: Interdiszciplináris Orvostudományok Doktori Iskola
Tudományterület / tudományág: orvostudományok > klinikai orvostudományok
Idegen nyelvű cím: Effects of a novel inhibitor of lipid peroxidation on injury caused by oxidative stress and ischemia-reperfusion
Témavezető neveBeosztás, tudományos fokozat, intézményEmail
Dr. Leprán IstvánDsc, SZTE Farmakológiai és Farmakoterápiai Intézetlepran.istvan@med.u-szeged.hu
EPrint azonosító (ID): 3087
Publikációban használt név : Dr. Nagy András
A mû MTMT azonosítója: 1384092
A feltöltés ideje: 2016. júl. 04. 12:11
Utolsó módosítás: 2016. júl. 04. 12:11
URI: http://doktori.bibl.u-szeged.hu/id/eprint/3087
Védés állapota: védett

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