Supervisors info:
Ιωάννα Ανδρεάδου, Αναπληρώτρια Καθηγήτρια, Τμήμ. Φαρμακευτικής ΕΚΠΑ,
Εμμανουήλ Μικρός, Καθηγητής, Τμήμα Φαρμακευτικής ΕΚΠΑ
Summary:
Doxorubicin (DXR) is a widely used antineoplastic drug whose action is followed by cardiotoxicity which in turn may lead to irreversible heart failure. Levosimendan (LEVO) is an inotropic and vasodilator drug, indicated for the short-term treatment of chronic heart failure as well as in cases where conventional treatment is considered ineffective.
In this study, the effect of levosimendan (LEVO) on chronic heart failure in relation to doxorubicin-induced cardiotoxicity (DXR) is examined. We present, the NMR based metabonomic analysis, of rat myocardial tissue after combined administration of levosimendan and doxorubicin.
Methods: 40 male Wistar rats were randomized into 5 groups. Control group received only N/S 0.9% 10 mL/kg i.p., DXR group received DXR 20 mg/kg i.p., DXR+LEVOA group was treated with LEVO 12 μg/kg i.p. and then received DXR 20 mg/kg i.p., DXR+LEVOB group was treated with LEVO 24 μg/kg i.p. and then received DXR 20 mg/kg, i.p., DXR+LEVOB+5-Hydroxydecanoic acid (5-HD) group was treated with LEVO 24 μg/kg i.p. and then received DXR 20 mg/kg, i.p., 5-HD was administered all three days of the test at a dose of 40 mg/kg*d i.p. The first dose of 5-HD should be given immediately before LEVO and DXR.
Right after the administration protocol (DXR, LEVO, 5-HD & N/S), while being anaesthetized, an echocardiogram was performed on all rats,. Τhen, through chest incision, hearts were removed and myocardial tissues were extracted (CHCl3/MeOH/H2O system). Metabolic profiles of the aqueous extracts were determined using Nuclear Magnetic Resonance (NMR) and analyzed using multivariate statistical analysis.
The metabolic profile analysis showed that cotreatment with DXR & LEVO alters the energy metabolites (ATP, ADP, AMP, IMP & Inosine) as well as metabolites related to glycolysis (glucose, alanine, lactate). Most importantly NAD+ was decreased while niacinamide was increased. The BCAA (leucine, valine, isoleucine) are increased in all groups compared to control.
The above results imply that in group DXR+LEVOB, mitochondrial metabolic salvage pathways are triggered as revealed by NAD+/niacinamide ratio change, which is related to cardiomyocyte protection, while preventing doxorubicin-induced anaerobic glycolysis. LEVO however fails to inhibit the potential catabolism of myocardial proteins.
Keywords:
Doxorubicin, Levosimendan, 5-Hydroxydecanoic acid, Metabonomics, Cardiotoxicity, Cardioprotection