الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Drug-induced cardiotoxicity (DIC) represents a significant adverse effect associated with various clinically important medications, particularly antineoplastic agents. Historically, this toxicity has led to the withdrawal of numerous drugs post-marketing and continues to restrict the therapeutic effectiveness of other valuable drugs. The assessment of cardiotoxic potential is now a crucial factor in drug development, prompting the establishment of various models to predict and mitigate such risks. DIC is a predominant reason for the discontinuation of compounds during both preclinical and clinical stages of drug development and is acknowledged as one of the most severe adverse effects in the introduction of new pharmaceuticals. This toxicity is a well-known risk factor across several classes of drugs.
Anthracyclines, including doxorubicin (DOX), are widely recognized chemotherapeutic agents linked to cardiotoxicity. DOX, despite being one of the most effective antineoplastic drugs, has its clinical use significantly limited due to its potential for dose-dependent cardiotoxicity. The mechanisms behind DOX-induced cardiotoxicity remain poorly understood. More critically, there are currently no effective therapeutic strategies to counteract DOX-induced cardiomyopathy, underscoring the urgent need for preventive measures against this serious condition.
Dexrazoxane (DEX), a cardioprotective drug, has been found to successfully mitigate cardiac damage induced by anthracycline-based chemotherapy medications (such as doxorubicin), it reduces the cardiotoxic effects by attaching to both unbound and bound iron, resulting in a decrease in the creation of anthracycline-iron complexes. As a result, this hinders the production of reactive oxygen species, which have the potential to harm the adjacent cardiac tissue.
Blueberries (BB) are valued for their abundant anthocyanin content. Anthocyanins are a specific type of polyphenolic chemical that is well-known for its positive impact on health. Blueberries possess polyphenols that exhibit antidiabetic, antibacterial, and anticarcinogenic characteristics.
The objectives of this study were to compare the protective effects of Dexrazoxane (DEX) and blue berry extract against the cardiomyopathy induced by Doxorubicin (DOX) in rats and to investigate whether DEX alone or in combination with BB extract could prevent DOX-induced cardiac dysfunction and ameliorate DOX-induced mitochondrial damage in the heart.
This research methodology involved the use of Wistar male albino rats, divided into seven distinct groups based on different treatment regimens: a control group, a DOX-only group, groups treated with either dexrazoxane or blueberry extract alone, and groups receiving combinations of these treatments with DOX. Over the course of the study, several parameters were assessed, including cardiac biomarkers, oxidative stress markers, inflammatory cytokines, and histopathological changes in myocardial tissues.
The study findings revealed significant cardioprotective effects when combining dexrazoxane (DEX) and blueberry extract (BB) with doxorubicin (DOX), notably in reducing cardiac injury as evidenced by the substantial decrease in cardiac biomarkers. Cardiac biomarkers such as cardiac troponin-T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and myeloperoxidase (MPO) are critical indicators of cardiac stress and damage. In rats treated with both DEX and BB alongside DOX, levels of these biomarkers were significantly lower compared to those treated with DOX alone. This substantial decrease in cTnT, NT-proBNP, and MPO levels in the combination therapy group indicates a notable reduction in cardiac stress and injury. The dual action of DEX and BB—where DEX acts as a chelating agent to reduce iron-mediated oxidative damage, and BB contributes antioxidant properties to combat oxidative stress—provides a robust shield against the cardiotoxic effects of DOX. Consequently, this combination therapy not only preserves cardiac function but also enhances the heart’s resilience against the oxidative and inflammatory insults typically induced by doxorubicin treatment.
Moreover, the combination of DEX and BB demonstrated a profound impact on oxidative stress markers within cardiac tissues. Malondialdehyde (MDA), a primary marker of lipid peroxidation, showed marked decreases in the combination treatment groups, indicating reduced oxidative damage to cellular membranes. Conversely, levels of glutathione (GSH) and superoxide dismutase (SOD), key components of the cellular antioxidant defense system, were notably higher in these groups. GSH, a major intracellular antioxidant, plays a crucial role in neutralizing reactive oxygen species and maintaining redox balance, while SOD catalyzes the dismutation of superoxide radicals into oxygen and hydrogen peroxide, thereby mitigating oxidative stress.
Additionally, the combined treatment favorably influenced the expression of critical genes involved in oxidative stress regulation and cellular defense mechanisms. There was an upregulation of Nrf2, a master regulator of antioxidant response element (ARE)-mediated gene expression, which enhances cellular resistance to oxidants. Simultaneously, the study observed a downregulation of miR-140-5p, a microRNA that can negatively impact antioxidant gene expression by targeting Nrf2. The modulation of these genetic pathways highlights the synergistic effect of DEX and BB in enhancing cellular defenses against DOX-induced oxidative stress.
Histopathological examinations provided visual confirmation of these biochemical data, presenting less structural damage and better preservation of myocardial architecture in the combination therapy groups compared to the DOX-only group. Microscopic analyses of cardiac tissue sections revealed less myocyte necrosis, reduced interstitial fibrosis, and fewer inflammatory infiltrates. This preservation of cellular integrity and structure further underscores the protective effects of DEX and BB against the cardiotoxic impact of DOX.
Overall, the integration of DEX and BB in the treatment regimen for DOX-administered rats not only reduced biomarkers of cardiac damage but also enhanced the cardiac antioxidant defenses and maintained better structural integrity of the heart tissue. These findings provide a compelling argument for the potential clinical benefits of this combination therapy in reducing the cardiotoxic side effects of doxorubicin in cancer treatment protocols.
Conclusions