الفهرس 
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Abstract
Background: Previous studies determined that doxorubicin-induced cardiomyopathy was associated with several mechanisms including; free radical damage, calcium overload, iron metabolism abnormality, DNA damage and cell apoptosis induced by doxorubicin. Extensive oxidative stress triggers extensive DNA breakage, PARP over-activation and consequent depletion of the cellular stores of its substrate NAD+ and ATP with consequent cell dysfunction and death by necrosis. Therefore, pharmacological inhibition of PARP preserves cellular NAD+ and ATP pools in oxidatively stressed cardiomyocytes. The aim of the work: The present study aims to detect the potential cardioprotective effect of inhibiting PARP apoptotic pathway by olaparib on cardiomyocytes’ oxidative stress, Ca+2 overload and cell necrosis, in comparison to dexrazoxane, in a mouse model of doxorubicin-induced cardiomyopathy. Materials and Methods: Seventy-two male BALB/c mice were randomized into six groups (12 per group). Cardiomyopathy was induced using doxorubicin 2.5 mg/kg i.p. administered every other day for 12 days, for a total cumulative dose of 15 mg/kg, then waiting for 4 weeks after the last doxorubicin injection. Groups 3,4.5 &6 treated with dexrazoxane (25 mg/kg), olaparib (5 mg/kg), olaparib (10 mg/kg) & olaparib (50 mg/kg), respectively. Results: The present data suggested that myocardial PARP-1 pathway inhibition by olaparib at a dosage of 10 mg/kg/d OR dexrazoxane, offered multiple cardioprotective mechanisms against DOX-CM through enhancement of calcium uptake by upregulation of SERCA2a mRNA gene expression, inhibition of myocardial oxidative damage and subsequent fibrosis. Despite that olaparib at a dosage of 5 mg/kg/d, halted doxorubicin-related myocardial remodeling, improved oxidative damage and calcium transport, the dose was small to effectively inhibit cleaved PARP-1 protein expression and provided non significant change of MST or weight loss. Olaparib at a dosage of 50 mg/kg/d couldn’t prevent doxorubicin induced cardiac remolding, despite enhancing oxidative damage, SERCA2A mRNA expression and inhibiting cleaved PARP-1 protein expression. Furthermore, it showed the least MST and the most profound weight loss. This group only between all treated ones, showed a deterioration in red cell indices and serum creatinine level. Conclusion: the current study detected the cardioprotective effect of myocardial PARP-1 pathway inhibition by Olaparib at a dosage of 10 mg/kg/d. This dose offered multiple cardioprotective mechanisms against DOX-CM through enhancement of calcium uptake by upregulation of SERCA2a mRNA gene expression, inhibition of myocardial oxidative damage and subsequent fibrosis. Also, the present study proved for the first time that dexrazoxane targets PARP-1 in heart, offering a newly discovered cardioprotective mechanism against DOX cardiotoxicity.