Acute doxorubicin cardiotoxicity is successfully treated with the phytochemical oleuropein through suppression of oxidative and nitrosative stress.
Oleuropein (oleu) is a natural phenolic antioxidant, which is present in elevated concentration in olives, olive oil and olive tree leaves. Doxorubicin (DXR) induced cardiotoxicity is mainly induced by oxidative stress but the precise mechanism remains obscure. However, there is evidence that high concentration of nitric oxide (NO) occurring as a result of iNOS induction and peroxynitrite formation may be involved in DXR cardiotoxicity. The aim of the present study was to evaluate a possible protective role of oleu in DXR induced cardiotoxicity in vivo. Fifty rats were divided into 6 groups and treated as follows: control group with a single injection of 2 ml normal saline intraperitoneally (i.p.), DXR group with a single dose of 20 mg/kg i.p, and DXR plus oleu groups with 20 mg/kg DXR i.p. and 100 or 200 mg/kg/BW of oleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Seventy-two hours after DXR treatment blood samples were collected for creatine phosphokinase (CPK), creatine phosphokinase-MB (CPK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) assessments and the rats were then sacrificed. Hearts were used for general histology, iNOS immunohistochemical and Western blot analysis, and for determination of tissue concentrations of lipid peroxidation products, protein carbonyls (PCs), and nitrotyrosine (NT). DXR treated animals demonstrated very extensive cytoplasmic vacuolisation whereas much less vacuolisation was found in oleu treated groups. They also revealed a significant elevation of cardiac enzymes release into systemic circulation (P<0.05 vs saline). Both doses of Oleu tested and both treatment protocols reduced DXR elevated serum levels of CPK, CPK-MB, LDH, AST and ALT (P<0.05). Furthermore, it reduced DXR induced lipid peroxidation, PCs content, NT concentration and iNOS induction in myocardial tissue (P<0.05). Oleu exerts a protective effect by eliminating DXR induced cardiotoxicity expressed by the alteration of intracellular and peripheral markers. Combined oleu and DXR treatment improves the therapeutic outcome by preventing undesirable toxicity.
Andreadou
Ioanna
I
Second University Department of Cardiology, Medical School, Attikon General Hospital, University of Athens, Rimini 1, 124 62 Athens, Greece. jandread@pharm.uoa.gr <jandread@pharm.uoa.gr>
Sigala
Fragiska
F
Iliodromitis
Efstathios K
EK
Papaefthimiou
Maria
M
Sigalas
Constantinos
C
Aligiannis
Nektarios
N
Savvari
Paraskevi
P
Gorgoulis
Vassilis
V
Papalabros
Efstathios
E
Kremastinos
Dimitrios Th
DT
D000208:Acute Disease; D000818:Animals; D004317:Doxorubicin / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D057888:Iridoid Glucosides; D039823:Iridoids; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015538:Nitrosation; D029592:Oleaceae / Q000737:chemistry*; D018384:Oxidative Stress; D011714:Pyrans / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
D057888:Iridoid Glucosides; D039823:Iridoids; D009566:Nitrates; D011714:Pyrans; C002769:oleuropein; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II