Background: The clinical effectiveness of doxorubicin (DOX), a widely used anthracycline chemotherapeutic agent, is limited by its well-documented cardiotoxicity. Oxidative stress, disruption of topoisomerase II (TOP II) signaling, and impaired endogenous antioxidant defenses contribute significantly to DOX-induced myocardial injury. Natural antioxidants such as blueberry (BB) extract and approved cardioprotective agents like Dexrazoxane (DEX) have been investigated for their potential protective effects.
Objective: To evaluate the cardioprotective effects of blueberry extract and Dexrazoxane—individually and in combination—against DOX-induced cardiotoxicity in Wistar rats.
Methods: Seven groups of Wistar rats (n = 8 each) were assigned to: Control, DOX control (18 mg/kg on day 11), BB extract (80 mg/kg), DEX (180 mg/kg), BB + DOX, DEX + DOX, and a combined BB + DEX + DOX group. Animals received treatments for 14 days, and DOX was administered intraperitoneally on day 11. Serum biomarkers (cTnT, NT-proBNP, MPO), cardiac oxidative stress markers (MDA, GSH, SOD), and TOP II expressions were assessed. Gene expressions of miR-140-5p, Sirt2, and Nrf2 were evaluated. Histopathological examination of cardiac tissues was performed to corroborate biochemical findings.
Results: The DOX control group showed significant elevation of cTnT, NT-proBNP, MPO, cardiac MDA, and TOP II, accompanied by marked reductions in GSH and SOD levels. DOX also induced upregulation of miR-140-5p and downregulation of Sirt2 and Nrf2. All treated groups demonstrated significant reversal of these alterations compared with the DOX control, with the combined BB + DEX + DOX group showing the most pronounced protection. Histopathological assessment supported the biochemical improvements observed.
Conclusion: Blueberry extract at 80 mg/kg provides substantial protection against DOX-induced cardiac oxidative stress and, especially when combined with Dexrazoxane, offers potent cardioprotective effects. These findings highlight its potential as an adjunct therapy to mitigate cardiotoxicity in patients undergoing anthracycline chemotherapy.