Cardioprotective activity of melatonin and its novel synthesized derivatives on doxorubicin-induced cardiotoxicity

Ahmed, Hanaa H.; Mannaa, Fathia A.; Elmegeed, Gamal A.; Doss, S. H.

doi:10.1016/j.bmc.2004.10.066

Cited by 67 publications

(32 citation statements)

References 46 publications

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“…It is noteworthy, although not a focus of this review, that as Tns have become effective biomarkers for occurrence, severity and monitoring of myocardial injury associated with various cardiac diseases, they have thus become efficacy or pharmacodynamic biomarkers of drugs that target such diseases [15][16][17][18][19][20]. Furthermore, as indicated below, they are translatable efficacy biomarkers that can be used in animal models of human diseases in drug discover,y as well as in clinical trials and postmarketing monitoring of patient treatment.…”

Section: Arrival Of Tnmentioning

confidence: 99%

“…Epinephrine/norepinephrine T Rat [113] Isoprenaline T, BCA Rat [52,114] Orciprenaline T Rat [59,115] Isoproterenol Bay, LDI, BV, TRI Rat [1,17] Dobutamine Bay Dog [1] Anthracyclines and anthraquinones Daunorubicin T Rabbit [48,116] Doxorubicin Human [117] T M o u s e [12] BCA, DRG Rat [18,51,56,57,118] T D o g [58,102] Mitoxantrone T Rat [15] Alcohol T Rat [16] Cobra venom T Mouse [119] Organophosphate -methidathion Bay Rat [19] …”

Section: Ischemia-reperfusion Injurymentioning

confidence: 99%

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Blood cardiac troponin in toxic myocardial injury: archetype of a translational safety biomarker

O’Brien¹

2006

Expert Review of Molecular Diagnostics

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A translational safety biomarker for toxic myocardial injury is needed in drug discovery and development. This need reflects the increasing recognition of occurrence of cardiotoxicities, prior lack of preclinical blood biomarkers for toxic cardiac injury, introduction of troponin as a biomarker, and regulatory and industry drivers. Cardiac troponin is considered the gold-standard biomarker in humans for cardiac injury due to ischemic injury and drug toxicity. It has been demonstrated to correlate highly with histopathological extent of injury, degree of impairment of cardiac function, and prognosis. Numerous studies have now clearly demonstrated that both cardiac troponin T and cardiac troponin I are sensitive and specific biomarkers of cardiac injury in laboratory animals. Their use is highly recommended for incorporation into preclinical drug-safety studies, especially whenever there is any history of cardiac effect in prior studies with a compound of the same or similar chemical or pharmacological class. The main caveats with respect to cross-species use of specific cardiac troponin assays are the need for species-specific validation, definition of cut-offs based on relevant assessments of imprecision and reference ranges or concurrent controls, and knowledge of the species-dependent kinetics of release into, and clearance from, the blood. Future development of high-sensitivity assays should determine whether minimal increases below a threshold concentration of troponin might reflect reversible myocardial effects.

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Section: Arrival Of Tnmentioning

confidence: 99%

Section: Ischemia-reperfusion Injurymentioning

confidence: 99%

Blood cardiac troponin in toxic myocardial injury: archetype of a translational safety biomarker

O’Brien¹

2006

Expert Review of Molecular Diagnostics

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“…This DOX-Fe 3+ complex can reduce oxygen to hydroxyl radical and other reactive oxygen species (ROS) [5] , which initiate severe damage to cardiac tissues. Efforts have been made to prevent the DOX cardiotoxicity with a number of antioxidants and iron chelators such as melatonin [6] and ICL670A (deferasirox) [7] . So far there is only one agent, dexrazoxane (Zinecard), approved by the Food and Drug Administration (FDA) to prevent cardiomyopathy induced by DOX.…”

Section: Introductionmentioning

confidence: 99%

Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

Jin

Pan

et al. 2006

Acta Pharmacologica Sinica

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Aim: To investigate the effects of deferiprone on doxorubicin-induced cardiotoxicity and determine its protection on cardiac contractility in vivo at tissue level. Methods: Spontaneously-beating isolated atria from rats were pretreated with deferiprone for 10 min at 1.2 mmol/L or 0.3 mmol/L, respectively before co-incubation with doxorubicin (DOX) at 0.03 mmol/L for 60 min. Contractility (dF/dt) was assessed every 10 min during the incubation. After that, the tissues around the sinuatrial nodes were fixed for ultrastructural study; succinate dehydrogenase (SDH) and Cu, Zn superoxide dismutase (Cu, Zn-SOD) activity, as well as malondialdehyde (MDA) level of the atria were assayed. Results: Treatment with DOX alone resulted in a 49.34% reduction of the contractility, mitochondria swelling, disruption of mitochondrial crista and decreased electron density of the matrices. Conversely, with the presence of deferiprone, the negative inotropic effect and lesions in the cardiac mitochondria structure induced by DOX were attenuated. Cu, Zn-SOD activity increased by 12.97%-12.11%, the MDA level decreased by 29.12%-39.82% and succinate dehydrogenase (SDH) activity was ameliorated by 25.15%-34.76%. Conclusion : Deferiprone can efficiently preserve cardiac contractility. Moreover, the results of this study indicate that deferiprone is able to protect mitochondrial function and structure form damage induced by DOX. This cardiac protective potential of deferiprone could be due to its defense capability against oxidative damage.

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“…Dox-induced cardiotoxicity results from a series of adverse reactions involving increased oxidative stress, alteration in cellular energetics, and initiation of cell death pathways (39,57,59). Numerous reports have demonstrated moderate protection against Dox-induced cardiotoxicity, yet the exact mechanism(s) and optimal therapy remain unknown (3,6,7,9,31).Recently, we reported (48, 50) that enhanced postischemic recovery of left ventricular (LV) function and reduced cardiac injury are found in transgenic (Tr) mice that overexpress human CYP2J2 and in mice with targeted deletion of soluble epoxide hydrolase. Whether the overexpression of CYP2J2 can protect against Dox-induced cardiotoxicity has not been investigated.…”

mentioning

confidence: 98%

mentioning

confidence: 98%

Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity

Zhang¹,

El‐Sikhry²,

Chaudhary³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Human cytochrome P-450 (CYP)2J2 is abundant in heart and active in biosynthesis of epoxyeicosatrienoic acids (EETs). Recently, we demonstrated that these eicosanoid products protect myocardium from ischemia-reperfusion injury. The present study utilized transgenic (Tr) mice with cardiomyocyte-specific overexpression of human CYP2J2 to investigate protection toward toxicity resulting from acute (0, 5, or 15 mg/kg daily for 3 days, followed by 24-h recovery) or chronic (0, 1.5, or 3.0 mg/kg biweekly for 5 wk, followed by 2-wk recovery) doxorubicin (Dox) administration. Acute treatment resulted in marked elevations of serum lactate dehydrogenase and creatine kinase levels that were significantly greater in wild-type (WT) than CYP2J2 Tr mice. Acute treatment also resulted in less activation of stress response enzymes in CYP2J2 Tr mice (catalase 750% vs. 300% of baseline, caspase-3 235% vs. 165% of baseline in WT vs. CYP2J2 Tr mice). Moreover, CYP2J2 Tr hearts exhibited less Dox-induced cardiomyocytes apoptosis (measured by TUNEL) compared with WT hearts. After chronic treatment, comparable decreases in body weight were observed in WT and CYP2J2 Tr mice. However, cardiac function, assessed by measurement of fractional shortening with M-mode transthoracic echocardiography, was significantly higher in CYP2J2 Tr than WT hearts after chronic Dox treatment (WT 37 +/- 2%, CYP2J2 Tr 47 +/- 1%). WT mice also had larger increases in beta-myosin heavy chain and cardiac ankryin repeat protein compared with CYP2J2 Tr mice. CYP2J2 Tr hearts had a significantly higher rate of Dox metabolism than WT hearts (2.2 +/- 0.25 vs. 1.6 +/- 0.50 ng.min(-1).100 microg protein(-1)). In vitro data from H9c2 cells demonstrated that EETs attenuated Dox-induced mitochondrial damage. Together, these data suggest that cardiac-specific overexpression of CYP2J2 limited Dox-induced toxicity.

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Cardioprotective activity of melatonin and its novel synthesized derivatives on doxorubicin-induced cardiotoxicity

Cited by 67 publications

References 46 publications

Blood cardiac troponin in toxic myocardial injury: archetype of a translational safety biomarker

Blood cardiac troponin in toxic myocardial injury: archetype of a translational safety biomarker

Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity

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