Ellagic acid protects against arsenic trioxide–induced cardiotoxicity in rat

Abstract

Arsenic trioxide (AsO) is utilized for treating patients suffering from hematological malignancies particularly acute promyelocytic leukemia. Unfortunately, the extensive application of this chemotherapeutic agent has been limited due to its adverse effects such as cardiotoxicity. Ellagic acid, as a phenolic compound, has shown to exert antioxidant, anti-inflammatory, antifibrotic, and antiatherogenic properties. It is also capable of protecting against drug toxicity. In this study, we evaluated whether ellagic acid can protect against AsO-induced heart injury in rats. Thirty-two male Wistar rats were randomly divided into four treatment groups, that is, control (0.2 mL of normal saline, intraperitoneally (ip)), AsO (5 mg/kg, ip), AsO plus ellagic acid, and ellagic acid (30 mg/kg, orally) groups. The drugs were administered daily for 10 days and pretreatment with ellagic acid was performed 1 h prior to AsO injection. Cardiotoxicity was characterized by electrocardiological, biochemical, and histopathological evaluations. Our results showed that ellagic acid pretreatment significantly ameliorated AsO-induced increase in glutathione peroxidase activity and malondialdehyde concentration ( p < 0.05 and p < 0.001, respectively) and also diminished QTc prolongation ( p < 0.0001) and cardiac tissue damages. Pretreatment with ellagic acid also lowered the increased troponin I ( p < 0.0001) and creatine kinase isoenzyme MB ( p < 0.01) levels in response to AsO. In conclusion, results of this study demonstrated that ellagic acid has beneficial cardioprotective effects against AsO toxicity. It is suggested that the protective effects were mediated by antioxidant properties of ellagic acid.

Antioxidants Protect against Arsenic Induced Mitochondrial Cardio-Toxicity

“…Dose selection justifications varied between studies, but generally, in vivo doses were selected based on the literature [ 33 , 52 , 53 , 54 , 55 ]. For example, as a fraction of the lethal dose [ 56 ], or experimentally as the minimum dose that induced cardio-toxic effects [ 57 ].…”

“…In vitro arsenic doses were selected based on significant detrimental effects on cell viability and/or cell death and were further stratified by exposure duration ( Table 1 ). The studies presented in this review utilized arsenic trioxide (As 2 O 3 ) [ 32 , 45 , 53 , 54 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ] or sodium arsenite (NaAsO 2 ) ( Figure 2 ) [ 49 , 55 , 56 , 67 , 68 , 69 , 70 , 71 ] at in vivo doses ranging from 0.8 mg/kg/day to 5 mg/kg/day administered intravenously or 2 mg/kg/day to 50 mg/kg/day administered orally for durations of 6 to 56 days. Experimental animals included Sprague Dawley rats [ 49 , 55 , 70 ], Wistar rats [ 59 , 67 ], BABL/c mice [ 72 ], APO E-/- mice [ 71 ], and guinea pigs [ 58 ].…”

“…In vivoarsenic exposure increased arsenic deposition in the heart [ 53 ], caused QT interval prolongation [ 70 ], increased QTc interval [ 54 ], induced ST-T wave change [ 62 ], prolonged PQ interval [ 59 ], increased RR and QRS interval [ 70 ], inhibited I KS current [ 58 ], reduced I K amperage [ 58 ] decreased heart rate [ 70 ], decreased cardiac output [ 64 ], and decreased 3′-5′-cyclic adenosine monophosphate (cAMP), an intracellular messenger that mediates catecholaminergic control of heart rate and contractility [ 74 ]. Arsenic exposure increased triglycerides [ 55 ], total cholesterol [ 67 ], and LDL cholesterol [ 70 ], and decreased HDL cholesterol in blood plasma [ 68 ].…”

A Pharmacological Update of Ellagic Acid

“…This indicates not only that diabetes mellitus-induced myocardial diastolic dysfunction is partly caused by reduction of sarco-endoplasmic reticulum Ca 2+ -ATP ase function, but also that it can be ameliorated by ellagic acid and other activators [213]. Ellagic acid exerts a cardioprotective effect against As 2 O 3 toxicity, a consequence of its antioxidant properties, which in this case enhance the endogenous antioxidant system [214]. It also protects against doxorubicin-induced cardiotoxicity in mice [215].…”

Antiinflammatory and anti‐cancer activities of pomegranate and its constituent, ellagic acid: Evidence from cellular, animal, and clinical studies

“…EA prevented the serum cardiac markers, MDA and NO levels, while increased the levels of GSH content, and CAT, SOD and GPx activities in the heart of rats (Goudarzi et al, ). Additionally, EA (30 mg/kg, orally) mitigated the levels of serum cardiac markers, MDA and QTc prolongation, and enhanced the level of GPx activity following the arsenic trioxide‐induced cardio‐toxicity in rat (Hemmati et al, ). It is suggested that the cardioprotective effects of EA may be through its antioxidant properties.…”