Abstract
BackgroundThe use of doxorubicin (DOX) an anthracycline antineoplastic agent is withdrawn due to its cardio-toxic side effects. Oxidative stress has been recognized as the primary cause of DOX induced cardiotoxicity. We have investigated whether polyphenol rich ethyl acetate extract of Acacia hydaspica (AHE) can attenuate doxorubicin-induced cardiotoxicity via inhibition of oxidative stress.MethodsAHE was administered orally to rats once daily for 6 weeks at doses of 200 and 400 mg/kg b.w. DOX (3 mg/kg b.w. i.p., single dose/week) was administered for 6 weeks (chronic model). The parameters studied to evaluate cardioprotective potential were the serum cardiac function biomarkers (CK, CKMB, AST and LDH), hematological parameters, cardiac tissue antioxidant enzymatic status and oxidative stress markers, and histopathological analysis to validate biochemical findings.ResultsChronic 6 week treatment of DOX significantly deteriorated cardiac function biomarkers and decreased the activities of antioxidant enzymes, whereas significant increase in oxidative stress biomarkers was noticed in comparison to control group. AHE dose dependently protected DOX-induced leakage of cardiac enzymes in serum and ameliorated DOX-induced oxidative stress; as evidenced by decreasing lipid peroxidation, H2O2 and NO content with increase in phase I and phase II antioxidant enzymes. Doxorubicin treatment produced severe morphological lesions, leucopenia, decrease in red blood cell counts and hemoglobin concentrations. AHE co-treatment protected the heart and blood elements from the toxic effects of doxorubicin as indicated by the recovery of hematological parameters to normal values and prevention of myocardial injuries in a dose dependent way. The protective potency of AHE (400 mg/kg b.w) was equivalent to silymarin.ConclusionResults revealed that AHE showed protective effects against DOX induce cardiotoxicity. The protective effect might attribute to its polyphenolic constituents and antioxidant properties. AHE might be helpful in combination therapies as safer and efficient.
Highlights
The use of doxorubicin (DOX) an anthracycline antineoplastic agent is withdrawn due to its cardio-toxic side effects
DOX did not cause significant decrease in heart weight/body weight (HW/Body weight (BW)) ratio, while significant decrease in body weight was noticed in rats treated with DOX alone or in combination with low dose Acacia hydaspica ethyl-acetate extract (AHE) (200 mg/kg b.w dose) compared to control group
Maximum restoration was observed in DOX + AHE (400 mg/kg.b.w) and DOX + Sily (100 mg/ kg b.w) groups as against the DOX group (Table 2)
Summary
The use of doxorubicin (DOX) an anthracycline antineoplastic agent is withdrawn due to its cardio-toxic side effects. Oxidative stress has been recognized as the primary cause of DOX induced cardiotoxicity. There appears to be multifactorial patho-mechanisms behind DOX-associated late cardiotoxicity, but predominantly oxidative stress is linked to redox cycling of the drug due to the overproduction of superoxide radicals (O2 − ·); which is the source for generating hydrogen peroxide and much more toxic hydroxyl radical and inducing oxidative stress [12,13,14]. Most the reactions involved in the DOX radical generation were catalyzed in the liver instead of heart, but due to relatively low antioxidant defense of cardiomyocytes makes the heart a most prominent target for DOX toxicity and the extent of the doxorubicin-persuaded oxidative trauma is up to 10 times higher in the cardiac tissue as compared to other tissues (liver, kidney, spleen). ROS lead to the peroxidation of myocyte membranes and, after calcium influx, into the intracellular space, which can lead to permanent myocyte damage [15]
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