Carnosic acid mitigates doxorubicin-induced cardiac toxicity: Evidence from animal and cell model investigations

Objective(s): Utilization of doxorubicin (DOX) as a chemotherapy medication is limited due to its cardiotoxic effects. Carnosic acid exerts antioxidant, anti-inflammatory, besides cytoprotective effects. The objective of this study was to investigate the ability of carnosic acid to protect rat hearts and the MCF۷ cell line against cardiotoxicity induced by DOX.Materials and Methods: The study involved the classification of male Wistar rats into seven groups: ۱) Control ۲) DOX (۲ mg/kg, every ۴۸h, IP, ۱۲d), ۳-۵) Carnosic acid (۱۰, ۲۰, ۴۰ mg/kg/day, IP, ۱۶d)+ DOX, ۶) Vitamin E (۲۰۰ mg/kg, every ۴۸h, IP, ۱۶d)+ DOX ۷) Carnosic acid (۴۰ mg/kg/day, IP, ۱۶d). Finally, cardiac histopathological alterations, ECG factors, carotid blood pressure, left ventricular function, heart-to-body weight ratio, oxidative (MDA, GSH), inflammatory (IL-۱β, TNF-α), plus apoptosis (caspase ۳, ۸, ۹, Bcl-۲, Bax) markers were evaluated. DOX toxicity and carnosic acid ameliorative effect were evaluated on MCF۷ cells using the MTT assay.Results: DOX augmented the QRS duration, QA, RRI, STI, and heart-to-body weight ratio, and reduced HR, LVDP, Min dP/dt, Max dP/dt, blood pressure, boosted MDA, TNF-α, IL۱-β, caspase ۳,۸,۹, Bax/Bcl-۲ ratio, decreased GSH content, caused fibrosis, necrosis, and cytoplasmic vacuolization in cardiac tissue but carnosic acid administration reduced the toxic effects of DOX. The cytotoxic effects of DOX were not affected by carnosic acid at concentrations of ۵ and ۱۰ μM.Conclusion: Carnosic acid as an anti-inflammatory and antioxidant substance is effective in reducing DOX-induced damage by enhancing antioxidant defense and modifying inflammatory signal pathway activity and can be used as an adjunct in treating DOX cardiotoxicity.

Keywords:

Anti-inflammatory agents , Antioxidants , Cardiotoxicity , Electrocardiography , Salvin , Vitamin E