Influence of a low-molecular-weight heparin derivative on the nitric oxide levels and apoptotic DNA damage in adriamycin-induced cardiac and renal toxicity

• Published in: Toxicology (Amsterdam) Vol. 217; no. 2; pp. 176 - 183
• Main Authors: Deepa, P.R., Varalakshmi, P.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 16-01-2006; Amsterdam Elsevier Science
• Subjects: Adriamycin; Animals; Antibiotics, Antineoplastic - toxicity; Anticoagulants - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Comet Assay; Cytotoxicity; DNA Damage; DNA Fragmentation - drug effects; Doxorubicin - toxicity; Electrophoresis, Agar Gel; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Heart - drug effects; Heart - physiopathology; Heart Diseases - chemically induced; Heart Diseases - metabolism; Heart Diseases - pathology; Heparin, Low-Molecular-Weight - pharmacology; Inflammation; Kidney - drug effects; Kidney - metabolism; Kidney - physiopathology; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Kidney Diseases - pathology; Low molecular weight heparin; Male; Medical sciences; Nitric Oxide - metabolism; Nitrites - blood; Rats; Rats, Wistar; Reactive nitrogen species; Reactive Nitrogen Species - metabolism; Toxicology; Tumor Necrosis Factor-alpha - chemistry; Tumor Necrosis Factor-alpha - metabolism; Adriamycin; DNA damage; Reactive nitrogen species; Low molecular weight heparin; Cytotoxicity; Inflammation; Apoptosis; Antineoplastic agent; Heart; Toxicity; Anticoagulant; Doxorubicin; Kidney; Isomerases; Species; DNA topoisomerase (ATP-hydrolysing); Enzyme; Enzyme inhibitor; Antibiotic; Urinary system; Cell death; Nitric oxide; Anthracyclins; Circulatory system; Lesion
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2005.09.009

The spectrum of the anti-apoptotic potential of heparin is currently under scrutiny in various tissues and under various pathological situations. In this study, the role of a low-molecular-weight heparin derivative (LMWH), certoparin in adriamycin-induced oxidative DNA damage has been evaluated in the cardiac and renal tissues. Two groups of male albino rats of the Wistar strain (140
±
10
g) received a single intravenous injection of adriamycin (7.5
mg/kg), and one of them received low-molecular-weight heparin (Certoparin Sodium, 300
μg/day/rat s.c.) treatment, commencing on day 8, continued for a week. The nitrosative stress in ADR cytotoxicity is indicated by the 1.51-fold cardiac and 2.36-fold renal increase in reactive nitrogen species (RNS), while LMWH treatment restores normalcy (
p
<
0.001). The influence of LMWH on the pro-inflammatory and pro-apoptotic cytokine, TNF-α was studied. Renal and cardiac levels of TNF-α showed a significant rise (
p
<
0.001) in the ADR cytotoxic group, while the TNF-α values departed towards control levels in the LMWH treated group (
p
<
0.001). DNA damage indicated by the fragmentation pattern (agarose gel electrophoresis) and the significantly increased comet tail length (
p
<
0.001) observed after alkaline single cell gel electrophoresis confirmed the toxicity induced by ADR on DNA in the untreated group. In the LMWH-treated group, the observation of intact DNA band after agarose gel electrophoresis, and the finding of comet tail length being comparable with that of the control substantiated the protection rendered by the LMWH, certoparin. In short, the results suggest that the low-molecular-weight heparin derivative, certoparin exerts beneficial effects on the nitrosative status, and on the biological macromolecules as DNA and curtails the rise of the pro-apoptotic and pro-inflammatory cytokine, TNF-α in the cardiac and renal tissues.