Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α
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Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague–Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1β mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1β), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.
KeywordsCardiotoxic Caspase-3 COX-II cTn-I Doxorubicin Fisetin
Atrial natriuretic peptide
Brain natriuretic peptide
Blood pressure per minute
Cardiac troponin I
Diastolic blood pressure
Inducible nitric oxide
- IL 1β
Left ventricular end-diastolic pressure
Left ventricular end-systolic pressure
Mean arterial blood pressure
Reactive oxygen species
Reverse transcription-polymerase chain reaction
Systolic blood pressure
Tumor necrosis factor-α
The authors would like to acknowledge Dr. S. S. Kadam, Chancellor, and Dr. K. R. Mahadik, Principal, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune for providing necessary facilities to carry out the study.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
The experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) of Poona College of Pharmacy, Pune and performed in accordance with the guidelines of Committee for Control and Supervision of Experimentation on Animals, Government of India on animal experimentation.
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