Álcool perílico previne danos causados pela cardiotoxidade aguda induzida por doxorrubicina em modelo animal

Abstract

Doxorubicin (DOX) is an anthracycline widely used in the treatment of various types of cancer, such as leukemia, lymphoma, breast cancer, and others, due to its high efficacy. However, its clinical use is associated with cardiovascular side effects, including toxicity. Oxidative stress plays a significant role in cardiotoxicity. In this context, substances derived from natural products, such as Perillyl Alcohol (PA), may mitigate these adverse effects. PA possesses various properties, including antioxidant, anti-inflammatory, and hepatoprotective activities. Thus, this study aimed to evaluate the potential cardioprotective effect of PA against acute cardiotoxicity induced by DOX in an animal model. Cardiotoxicity was induced with DOX (20 mg/kg, i.p.), and animals were treated with PA at doses of 50 or 100 mg/kg (i.p.). In vivo electrocardiogram analyses, serum myocardial injury markers, and blood count evaluations were conducted. Cardiac contractile function was assessed ex vivo using a Langendorff aortic perfusion system. Antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6, were measured in cardiac tissue. Histopathological damage was also evaluated. The animals were divided into the following groups: Control, DOX, PA 50 mg + DOX, PA 100 mg + DOX, and PA 50 mg groups. Animals treated with DOX exhibited electrocardiogram alterations, elevated levels of total creatine kinase (CK), creatine kinase MB isoform (CK-MB), and lactate dehydrogenase (LDH), leukopenia, reduced contractile force, increased malondialdehyde (MDA) concentration, and lipid hydroperoxides, as well as decreased sulfhydryl groups. Additionally, a reduction in the activity of antioxidant enzymes CAT, SOD, and GPx was observed, along with an increased inflammatory process, reflected in elevated levels of pro- inflammatory cytokines TNF-α, IL-1β, and IL-6. Pre-treatment with PA improved cardiac electrical activity by reducing RR, QT, QTc, and PR intervals and increased left ventricular developed pressure. Pre-treatment also modulated cellular redox status by enhancing GPx, SOD, and CAT activity, reducing MDA and total hydroperoxide formation, and preserving total sulfhydryl groups. It decreased CK, CK-MB, LDH levels, and leukopenia. Furthermore, PA modulated the inflammatory process initiated by DOX by adjusting TNF-α, IL-1β, and IL-6 levels. Additionally, it minimized histopathological alterations induced by DOX. Thus, PA treatment not only improved cardiac electrical activity and left ventricular contractile function but also positively modulated cellular redox status, reducing markers of oxidative stress and inflammation. Therefore, PA demonstrated antioxidant and anti-inflammatory properties, leading to cardioprotection.