الفهرس 
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Abstract
The aim of this study was to elucidate and compare the potential protective role of NAM and 1α(OH)D3 against DOX induced cardiotoxicity and to explore the possible molecular mechanism. The present study was divided into two parts. First: Screening the cardioprotective effect of NAM as well as 1α(OH)D3 against acute DOX cardiotoxicity. Second: Studying the cardioprotective effect of NAM and 1α(OH)D3 against chronic DOX cardiotoxicity
For screening the cardioprotective effect of NAM against acute DOX cardiotoxicity, 30 adult male rats were assigned to five groups as follow: control group, DOX group: rats were given a single i.p. injection of DOX (15 mg/kg) on the 7th day. The third, fourth & fifth groups (NAM groups): rats were given oral pretreatment of NAM at dose of 200, 400 and 600 mg/kg respectively for 7 days and the single i.p. DOX injection (15 mg/kg) on the 7th day after 1 h of the last treatment of NAM. For screening the cardioprotective effect of 1α(OH)D3 against acute DOX cardiotoxicity, 30 adult male rats were assigned to five groups as follow: control group, DOX group: rats were given a single i.p. injection of DOX (15 mg/kg) on the 7th day. Third group: were given i.p. injection of 1α(OH)D3at a dose of 0.5ug/Kg as pretreatment for 7 consecutive days and the single i.p. DOX injection on the 7th day after 1 h of the last treatment of 1α(OH)D3. The fourth group: were given single i.p. injection of 1α(OH)D3 at a dose of 0.5ug/Kg on the 5th day of the study only and i.p. DOX injection on the 7th day. The fifth group: were given single i.p. injection of 1α(OH)D3at a dose of 0.5ug/Kg one hour before i.p. DOX injection on the 7th day.
Based on serum cardiotoxicity markers as well as the histopathological examination, the optimal cardioprotective dose of NAM was 600 mg/kg and 1α(OH)D3 was 0.5 ug/kg 48 hours before DOX administration.
For studying the cardioprotective effect of NAM (600 mg/kg) and 1α(OH)D3 (0.5 ug/kg) against chronic DOX cardiotoxicity, sixty adult male Sprague Dawley rats were assigned randomly into six groups as follows; Control group were given distilled water through an oral gavage daily for 28 days., DOX group were given a single intraperitoneal (i.p.) injection of DOX (5 mg/kg) once a week for four consecutive weeks. The NAM+DOX group were given an oral dose of NAM (600 mg/kg) daily for 28 days and DOX (once weekly, 5mg/kg). The 1α(OH)D3+DOX group were given an i.p. injection of 1α(OH)D3 (0.5 ug/kg) once weekly, 48 hours before the DOX injection (once weekly, 5mg/kg) for four consecutive weeks. The NAM group were given NAM at an oral dose of 600 mg/kg daily for four consecutive weeks. The 1α(OH)D3group were given 1α(OH)D3 (0.5 ug/kg) i.p. once weekly for four consecutive weeks.
The present study showed that DOX induced significant myocardial damage in rats, which was characterized by ECG changes, increased cardiac index, elevated serum CK-MB and cTn-I levels, as well as, by deleterious histopathological alteration. Moreover, DOX-induced impairment in cardiac bioenergetics and intracellular Ca2+ overload was associated with activation of several Ca2+ dependent cysteine proteases CPN1 which in turn activated PARP. Mitochondrial Ca2+ overload was associated with triggering intrinsic apoptotic pathway where it significantly elevated BAX and caspase-3 and reduced Bcl-2. Furthermore, exaggerated inflammatory responses play vital roles in the pathogenesis of DOX-induced cardiomyopathy. In our study, DOX significantly elevated NF-kB and IL-6. On the other hand, CaMKII activation can trigger cardiomyocyte death by promoting Ca2+ flux from SR to the mitochondria resulting in mitochondrial permeability transition and consequently switching on the intrinsic apoptotic machinery. In our study, DOX significant elevated CAMKII indicating the activation of the apoptotic and inflammatory processes.
In conclusion, the current study proved the promising cardioprotective effects of NAM and 1α(OH)D3 against DOX-induced cardiomyopathy. Both NAM and 1α(OH)D3 ameliorated the cardiotoxic effects of DOX as evidenced by normalization of both cardiotoxicity indices and ECG abnormalities together with preserving histopathological features and ultrastructure architecture of cardiac tissues. Besides, the study has uncovered various molecular mechanisms responsible for these cardioprotective properties in the term of replenishing ATP stores, restoring intracellular and mitochondrial Ca2+ homeostasis, suppressing mitochondrial and CPN1- mediated apoptotic cascades and abrogating NF-κB - triggered inflammatory responses. Moreover, a novel finding of this study is exploring the inhibitory effect of both NAM and 1α(OH)D3 on the pivotal Ca2+ transducer CAMKII-δ which is extensively implicated in DOX-induced Ca2+ overload, inflammatory & apoptotic signals. Furthermore, our study clarifies that, NAM has a superior cardioprotective effect over 1α(OH)D3, regarding increasing ATP production, reducing both mitochondrial and cytosolic Ca2+ and downregulation of CAMKII-δ, CPN1, PARP and inflammatory markers. These findings advocated pharmacological benefits of both nutraceuticals as adjunctive therapy with DOX for halting the progression of its associated devastating cardiac complications Fig (S-1).