Melatonin protection against lethal myocyte injury induced by doxorubicin as reflected by effects on mitochondrial membrane potential.
Melatonin (MLT) is highly protective against cardiotoxicity caused by doxorubicin (DOX). DOX induces cardiac damage via production of reactive oxygen species. This study tests the hypothesis that oxygen radicals generated by DOX disrupt mitochondrial membrane potential (Delta(psi)(m)) prior to severe cell injury. Myocytes were incubated with 20 micromol/l DOX for 24 h. Myocyte damage was estimated by lactate dehydrogenase (LDH) release. Mitochondrial membrane potential was determined by staining myocytes with 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1) using confocal microscope. A significant amount of LDH was observed after 24 h of treatment with DOX. Mitochondria in DOX-treated myocytes exhibited a collapse of Delta(psi)(m). Pretreatment with melatonin (1 mmol/l) for one hour prevented the release of LDH and restored Delta(psi)(m). The data support the hypothesis that DOX induces damage to mitochondria through radicals, and this is reflected in depolarization of Delta(psi)(m), which was prevented by melatonin.
Xu
Meifeng
M
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45267-0529, USA.
Ashraf
Muhammad
M
D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002232:Carbocyanines / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D001562:Benzimidazoles; D002232:Carbocyanines; D005456:Fluorescent Dyes; D017382:Reactive Oxygen Species; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D008550:Melatonin; D010100:Oxygen