Cardiovascular Toxicology

, Volume 11, Issue 1, pp 78–88 | Cite as

A Combination of Melatonin and Alpha Lipoic Acid has Greater Cardioprotective Effect than Either of them Singly Against Cadmium-Induced Oxidative Damage

  • Raktim Mukherjee
  • Sudeep Banerjee
  • Niraj Joshi
  • Prem Kumar Singh
  • Darshee Baxi
  • A. V. Ramachandran
Article

Abstract

Present study evaluates cardioprotective role of melatonin (Mel), alpha lipoic acid (ALA), a combination of melatonin and alpha lipoic acid (Mel + ALA) against cadmium (Cd)-induced oxidative damage. Female albino rats were subjected to 15-day exposure to Cd (5.12 mg/kg bw) alone or treated with ML (10 mg/kg bw) + ALA (25 mg/kg bw) simultaneously. Plasma markers of cardiac damage, cardiac free radical generation, lipid peroxidation, endogenous antioxidant status, cadmium load, metallothionein induction, and histopathology were evaluated in various experimental groups. Combination of Mel + ALA significantly prevented leakage of marker enzymes of cardiac damage, changes in cardiac free radical generation, endogenous antioxidants, antioxidant status, structural alterations and augmented the degree of metallothionein (MT) induction. The results demonstrate that ML + ALA co-administration effectively protected against Cd-induced cardiac oxidative damage.

Keywords

Cadmium Metallothionein Melatonin Alpha lipoic acid Cardiotoxicity 

References

  1. 1.
    Lee, J., Heng, D., Chia, K. S., Chew, S. K., Tan, B. Y., & Hughes, K. (2001). Risk factors and incident coronary heart disease in Chinese, Malay and Asian Indian males: The Singapore Cardiovascular Cohort Study. International Journal of Epidemiolgy, 30, 983–988.CrossRefGoogle Scholar
  2. 2.
    Bhatnagar, A. (2006). Environmental cardiology: Studying mechanistic links between pollution and heart disease. Circulation Research, 99, 692–705.PubMedCrossRefGoogle Scholar
  3. 3.
    Subramanyam, G., Bhaskar, M., & Govindappa, S. (1992). The role of cadmium in induction of atherosclerosis in rabbits. Indian Heart Journal, 44, 177–180.PubMedGoogle Scholar
  4. 4.
    Smetana, R., Glogar, D., Weidinger, F., & Meisinger, V. (1987). Heavy metal and trace element deviations. A comparison of idiopathic dilated cardiomyopathy and coronary heart diseases. Wiener Medizinische Wochenschrift, 137, 553–557.PubMedGoogle Scholar
  5. 5.
    Balaraman, R., Gulati, O. D., Bhatt, J. D., Bhatt, S. D., Rathod, S. P., & Hemavati, K. G. (1989). Cadmium induced hypertension in rats. Pharmacology, 38, 226–234.PubMedCrossRefGoogle Scholar
  6. 6.
    Mollaoglu, H., Gokcimenb, A., Ozguner, F., Oktemd, F., Koyu, A., Kocak, A., et al. (2006). Caffeic acid phenethyl ester prevents cadmium-induced cardiac impairment in rat. Toxicology, 227, 15–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Manna, P., Sinha, M., & Sil, P. C. (2008). Amelioration of cadmium-induced cardiac impairment by taurine. Chemico-Biological Interactions, 174, 88–97.PubMedCrossRefGoogle Scholar
  8. 8.
    Millis, P. R., Ramsey, M. H., & John, E. A. (2004). Heterogeneity of cadmium concentration in soil as a source of uncertainty in plant uptake and its implications for human health risk assessment. Science of the Total Environment, 326, 49–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Chary, N. S., Kamala, C. T., & Raj, D. S. (2008). Assessing risk of heavy metals from consuming food grown on sewage irrigated soils and food chain transfer. Ecotoxicology and Environmental Safety, 69, 513–524.PubMedCrossRefGoogle Scholar
  10. 10.
    Ramachandran, A. V. (2003). Aftermath of Baroda effluent channel: Impact assessment along the channel and the Mahi estuary with reference to heavy metals, environment global changes and challenges (pp. 15–49). Jaipur: ABD Publishers.Google Scholar
  11. 11.
    Karbownik, M., & Reiter, R. J. (2000). Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proceedings of the Society for Experimental Biology and Medicine, 225, 9–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Lee, Y. M., Chen, H. R., Hsiao, G., Sheu, J. R., Wang, J. J., & Yen, M. H. (2002). Protective effects of melatonin on myocardial ischemia/reperfusion injury in vivo. Journal of Pineal Research, 33, 72–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Lochner, A., Genade, S., Davids, A., Ytrehus, K., & Moolman, J. A. (2006). Short- and long-term effects of melatonin on myocardial post-ischemic recovery. Journal of Pineal Research, 40, 56–63.PubMedCrossRefGoogle Scholar
  14. 14.
    Reiter, R. J. (2000). Melatonin: Lowering the high price of free radicals. News in Physiological Sciences, 15, 246–250.PubMedGoogle Scholar
  15. 15.
    Sahna, E., Olmez, E., & Acet, A. (2002). Effects of physiological and pharmacological concentrations of melatonin on ischemia-reperfusion arrhythmias in rats: Can the incidence of sudden cardiac death be reduced? Journal of Pineal Research, 32, 194–198.PubMedCrossRefGoogle Scholar
  16. 16.
    Tengattini, S., Reiter, R. J., Tan, D. X., Terron, M. P., Rodella, L. F., & Rezzani, R. (2008). Cardiovascular diseases: Protective effects of melatonin. Journal of Pineal Research, 44, 16–25.PubMedGoogle Scholar
  17. 17.
    Chan, T. Y., & Tang, P. L. (1996). Characterization of the antioxidant effects of melatonin and related indoleamines in vitro. Journal of Pineal Research, 20, 187–191.PubMedCrossRefGoogle Scholar
  18. 18.
    Anton-Tay, F., Martinez, I., Tovar, R., & Benitez-King, G. (1998). Modulation of the subcellular distribution of calmodulin by melatonin in MDCK cells. Journal of Pineal Research, 24, 35–42.PubMedCrossRefGoogle Scholar
  19. 19.
    Vanecek, J. (1995). Melatonin inhibits increase of intracellular calcium and cyclic AMP in neonatal rat pituitary via independent pathways. Molecular and Cellular Endocrinology, 107, 149–153.PubMedCrossRefGoogle Scholar
  20. 20.
    Iriti, M., Varoni, E. M., & Vitalini, S. (2010). Melatonin in traditional Mediterranean diets. Journal of Pineal Research, 49, 101–105.PubMedGoogle Scholar
  21. 21.
    Al-Majed, A. A., Gado, A. M., Al-Shabanah, O. A., & Mansour, M. A. (2002). Alpha-lipoic acid ameliorates myocardial toxicity induced by doxorubicin. Pharmacological Research, 46, 499–503.PubMedCrossRefGoogle Scholar
  22. 22.
    Gurer, H., Ozgunes, H., Oztezcan, S., & Ercal, N. (1999). Antioxidant role of [alpha]-lipoic acid in lead toxicity. Free Radical Biology and Medicine, 27, 75–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Packer, L., Tritschler, H. J., & Wessel, K. (1997). Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radical Biology and Medicine, 22, 359–378.PubMedCrossRefGoogle Scholar
  24. 24.
    Motawi, T. M. K., Sadik, N. A. H., & Refaat, A. (2010). Cytoprotective effects of DL-alpha-lipoic acid or squalene on cyclophosphamide-induced oxidative injury: An experimental study on rat myocardium, testicles and urinary bladder. Food and Chemical Toxicology, 48, 2326–2336.PubMedCrossRefGoogle Scholar
  25. 25.
    Beuge, J. A., & Aust, S. D. (1978). Microsomal lipid peroxidation. Methods in Enzymology, 52, 302–310.CrossRefGoogle Scholar
  26. 26.
    Holland, M. K., & Storey, B. T. (1981). Oxygen metabolism of mammalian spermatozoa. Generation of hydrogen peroxide by rabbit epididymal spermatozoa. Biochemical Journal, 198, 273–280.PubMedGoogle Scholar
  27. 27.
    Puntarulo, S., & Cederbaum, A. I. (1988). Effect of oxygen concentration on microsomal oxidation of ethanol and generation of oxygen radicals. Biochemical Journal, 251, 787–794.PubMedGoogle Scholar
  28. 28.
    Beutler, E., Duron, O., & Kelly, B. M. (1969). Improved method for the reduced glutathione. Journal of Laboratory and Clinical Medicine, 61, 882–888.Google Scholar
  29. 29.
    Omaye, S., Turnbull, J. D., & Sauberlich, H. E. (1979). Selected methods for the determination of ascorbic acid in animal cells, tissues and fluids. Methods in Enzymology, 62, 3–11.PubMedCrossRefGoogle Scholar
  30. 30.
    Desai, I. D. (1984). Vitamin E analysis methods for animal tissues. Methods in Enzymology, 105, 138–147.PubMedCrossRefGoogle Scholar
  31. 31.
    Marklund, S., & Marklund, G. (1974). Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. European Journal of Biochemistry, 47, 469–474.PubMedCrossRefGoogle Scholar
  32. 32.
    Sinha, A. K. (1972). Calorimetric assay of catalase. Analytical Biochemistry, 47, 389–394.PubMedCrossRefGoogle Scholar
  33. 33.
    Rotruck, J. T., Pope, A. L., Ganther, H. E., Swanson, A. B., Hafeman, D. G., & Hoekstra, W. G. (1973). Selenium biochemical role as a component of glutathione peroxidase. Science, 179, 588–590.PubMedCrossRefGoogle Scholar
  34. 34.
    Habig, W. H., Pabst, M. J., & Jakoby, W. B. (1974). Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. Journal of Biological Chemistry, 249, 7130–7139.PubMedGoogle Scholar
  35. 35.
    Zmudzki, J. (1977). Determination of lead in biological material by atomic absorption spectrophotometry (AAS). Medycyna Weterynaryjna, 33, 179–181.Google Scholar
  36. 36.
    Onosaka, S., & Cherian, M. G. (1982).The induced synthesis of metallothionein in various tissues of rats in response to metals. II. Influence of zinc status and specific effect on pancreatic metallothionein. Toxicology, 23, 11–20.Google Scholar
  37. 37.
    Chwelatiuk, E., Wlostowski, T., Krasowska, A., & Bonda, E. (2006). The effect of orally administered melatonin on tissue accumulation and toxicity of cadmium in mice. Journal of Trace Element and Medical Biology, 19, 259–265.CrossRefGoogle Scholar
  38. 38.
    Lowry, O. H., Rosenbrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with Folin phenol reagent. Journal of Biological Chemistry, 193, 265–275.PubMedGoogle Scholar
  39. 39.
    Shen, Y., Sangiah, S., & Ye, M. Y. (1995). Determination of hydroxyl radical formation in the testes of cadmium-treated mice by high performance liquid chromatography. Journal of Liquid Chromatography, 18, 2217–2228.CrossRefGoogle Scholar
  40. 40.
    Shi, H., Sui, Y., Wang, X., Luo, Y., & Ji, L. (2005). Hydroxyl radical production and oxidative damage induced by cadmium and naphthalene in liver of Carassius auratus. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 140, 115–121.CrossRefGoogle Scholar
  41. 41.
    Babusikova, E., Kaplan, P., Lehotsky, J., Jesenak, M., & Dobrota, D. (2004). Oxidative modification of rat cardiac mitochondrial membranes and myofibrils by hydroxyl radicals. General Physiology and Biophysics, 23, 327–335.PubMedGoogle Scholar
  42. 42.
    Jadeja, R. N., Thounaojam, M. C., Patel, D. K., Devkar, R. V., Ramachandran, A. V., et al. (2010). Pomegranate (Punica granatum L.) juice supplementation attenuates isoproterenol-induced cardiac necrosis in rats. Cardiovascular Toxicology, 10, 174–180.PubMedCrossRefGoogle Scholar
  43. 43.
    Stohs, S. J., Bagchi, D., Hassoun, E., & Bagchi, M. (2000). Oxidative mechanisms in the toxicity of chromium and cadmium ions. Journal of Environmental Pathology, Toxicology and Oncology, 19, 201–213.PubMedGoogle Scholar
  44. 44.
    Stohs, S. J., Bagchi, D., Hassoun, E., & Bagchi, M. (2001). Oxidative mechanisms in the toxicity of chromium and cadmium ions. Journal of Environmental Pathology, Toxicology and Oncology, 20, 77–88.PubMedGoogle Scholar
  45. 45.
    Zalups, R. K., & Barfuss, D. W. (1996). Nephrotoxicity of inorganic mercury co-administrated with l-cysteine. Toxicology, 109, 15–29.PubMedCrossRefGoogle Scholar
  46. 46.
    Martensson, J., & Meister, A. (1991). Glutathione deficiency decreases tissue ascorbate levels in newborn rats: Ascorbate spares glutathione and protects. Proceedings of the National Academy of Sciences USA, 88, 4656–4660.CrossRefGoogle Scholar
  47. 47.
    Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T., Mazur, M., & Telser, J. (2007). Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology, 39, 44–84.CrossRefGoogle Scholar
  48. 48.
    Clarke, M. W., Burnett, J. R., & Croft, K. D. (2008). Vitamin E in human health and disease. Critical Reviews in Clinical Laboratory Sciences, 45, 417–450.PubMedCrossRefGoogle Scholar
  49. 49.
    Manna, P., Sinha, M., & Sil, P. C. (2009). Taurine plays a beneficial role against cadmium-induced oxidative renal dysfunction. Amino Acids, 36, 417–428.PubMedCrossRefGoogle Scholar
  50. 50.
    Manca, D., Ricard, A. C., Trottier, B., & Chevalier, G. (1991). Studies on lipid peroxidation in rat tissues following administration of low and moderate doses of cadmium chloride. Toxicology, 67, 303–323.PubMedCrossRefGoogle Scholar
  51. 51.
    Sarkar, S., Yadav, P., Trivedi, R., Bansal, A. K., & Bhatnagar, D. (1995). Cadmium-induced lipid peroxidation and the status of the antioxidant system in rat tissues. Journal of Trace Elements and Medical Biology, 9, 144–149.Google Scholar
  52. 52.
    Hidalgo, H. A., & Bryan, S. E. (1977). Cadmium-115 bound to nuclear and cytoplasmic proteins. Toxicology and Applied Pharmacology, 42, 319–327.PubMedCrossRefGoogle Scholar
  53. 53.
    Adams, J. E., 3rd, Bodor, G. S., Davila-Roman, V. G., Delmez, J. A., Apple, F. S., Ladenson, J. H., et al. (1993). Cardiac troponin I. A marker with high specificity for cardiac injury. Circulation, 88, 101–106.PubMedGoogle Scholar
  54. 54.
    Burlina, A., Zaninotto, M., Secchiero, S., Rubin, D., & Accorsi, F. (1994). Troponin T as a marker of ischemic myocardial injury. Clinical Biochemistry, 27, 113–121.PubMedCrossRefGoogle Scholar
  55. 55.
    O’Brien, P. J., Dameron, G. W., Beck, M. L., Kang, Y. J., Erickson, B. K., Di Battista, T. H., et al. (1997). Cardiac troponin T is a sensitive, specific biomarker of cardiac injury in laboratory animals. Laboratory Animal Science, 47, 486–495.PubMedGoogle Scholar
  56. 56.
    Vorderwinkler, K. P., Mair, J., Puschendorf, B., Hempel, A., Schluter, K. D., & Piper, H. M. (1996). Cardiac troponin I increases in parallel to cardiac troponin T, creatine kinase and lactate dehydrogenase in effluents from isolated perfused rat hearts after hypoxia-reoxygenation-induced myocardial injury. Clinica Chimica Acta, 251, 113–117.CrossRefGoogle Scholar
  57. 57.
    Kopp, S. J., Barany, M., Erlanger, M., Perry, E. F., & Perry, H. M., Jr. (1980). The influence of chronic low-level cadmium and/or lead feeding on myocardial contractility related to phosphorylation of cardiac myofibrillar proteins. Toxicology and Applied Pharmacology, 54, 48–56.PubMedCrossRefGoogle Scholar
  58. 58.
    Haenen, G. R. M. M., Vermeulen, N. P. E., Timmerman, H., & Bast, A. (1989). Effect of thiols on lipid peroxidation in rat liver microsomes. Chemico-Biological Interactions, 71, 201–212.PubMedCrossRefGoogle Scholar
  59. 59.
    Sumathi, R., Baskaran, G., & Varalakshmi, P. (1996). Effect of DL [alpha]-lipoic acid on tissue redox state in acute cadmium-challenged tissues. The Journal of Nutritional. Biochemistry, 7, 85–92.CrossRefGoogle Scholar
  60. 60.
    Moini, H., Packer, L., & Saris, N.-E. L. (2002). Antioxidant and prooxidant activities of [alpha]-lipoic acid and dihydrolipoic acid. Toxicology and Applied Pharmacology, 182, 84–90.PubMedCrossRefGoogle Scholar
  61. 61.
    Reiter, R. J., Tan, D. X., Manchester, L. C., Lopez-Burillo, S., Sainz, R. M., & Mayo, J. C. (2003). Melatonin: Detoxification of oxygen and nitrogen-based toxic reactants. Advances in Experimental and Medical Biology, 527, 539–548.Google Scholar
  62. 62.
    Reiter, R. J., Tan, D. X., Qi, W., Manchester, L. C., Karbownik, M., & Calvo, J. R. (2000). Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo. Biological Signals and Receptors, 9, 160–171.PubMedCrossRefGoogle Scholar
  63. 63.
    Shida, C. S., Castrucci, A. M., & Lamy-Freund, M. T. (1994). High melatonin solubility in aqueous medium. Journal of Pineal Research, 16, 198–201.PubMedCrossRefGoogle Scholar
  64. 64.
    Cao, Z., Tsang, M., Zhao, H., & Li, Y. (2003). Induction of endogenous antioxidants and phase 2 enzymes by [alpha]-lipoic acid in rat cardiac H9C2 cells: Protection against oxidative injury. Biochemical Biophysical Research Communications, 310, 979–985.CrossRefGoogle Scholar
  65. 65.
    Klaassen, C. D., Liu, J., & Choudhuri, S. (1999). Metallothionein: An intracellular protein to protect against cadmium toxicity. Annual Reviews in Pharmacology and Toxicology, 39, 267–294.CrossRefGoogle Scholar
  66. 66.
    O’Brien, P. J., Dameron, G. W., Beck, M. L., & Brandt, M. (1998). Differential reactivity of cardiac and skeletal muscle from various species in two generations of cardiac troponin-T immunoassays. Research in Veterinary Science, 65, 135–137.PubMedCrossRefGoogle Scholar
  67. 67.
    Alonso-González, C., González, A., Mediavilla, D., Cos, S., Martínez-Campa, C., Sánchez-Barceló, E., et al. (2007). Melatonin prevents cadmium toxicity through activation of metallothionein I and II genes expression. Toxicology Letters. Abstracts of the 44th Congress of the European Societies of Toxicology 172, S205–S206.Google Scholar
  68. 68.
    Kang, Y. J. (1999). The antioxidant function of metallothionein in the heart. Proceedings for Society of Experimental Biology and Medicine, 222, 263–273.CrossRefGoogle Scholar
  69. 69.
    Kang, Y. J. (2007). Antioxidant defense against anthracycline cardiotoxicity by metallothionein. Cardiovascular Toxicology, 7, 95–100.PubMedCrossRefGoogle Scholar
  70. 70.
    Ou, P., Tritschler, H. J., & Wolff, S. P. (1995). Thioctic (lipoic) acid: A therapeutic metal-chelating antioxidant? Biochemical Pharmacology, 50, 123–126.PubMedCrossRefGoogle Scholar
  71. 71.
    Venkatachalam, S. R., Salaskar, A., Chattopadhyay, A., Barik, A., Mishra, B., Gangabhagirathi, R., Priyadarsini, K. I., et al. (2006). Synthesis, pulse radiolysis, and in vitro radioprotection studies of melatoninolipoamide, a novel conjugate of melatonin and [alpha]-lipoic acid. Bioorganic & Medicinal Chemistry. Tetrahedron Prize for Creativity in Organic Chemistry 14, 6414–6419 (2005: B. Giese).Google Scholar
  72. 72.
    Lopez-Burillo, S., Tan, D. X., Mayo, J. C., Sainz, R. M., Manchester, L. C., & Reiter, R. J. (2003). Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and alpha-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: A study of their individual and synergistic actions. Journal of Pineal Research, 34, 269–277.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Raktim Mukherjee
    • 1
    • 2
  • Sudeep Banerjee
    • 1
  • Niraj Joshi
    • 1
  • Prem Kumar Singh
    • 1
  • Darshee Baxi
    • 1
  • A. V. Ramachandran
    • 1
  1. 1.Division of Cardiotoxicity, Department of Zoology, Faculty of ScienceThe Maharaja Sayajirao University of BarodaVadodaraIndia
  2. 2.Shree PM Patel College of PG Studies and Research in ScienceAffiliated to SP UniversityAnandIndia

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