Skip to main content
SpringerLink
Log in

The Antioxidant Activity of Copper(II) (3,5-Diisopropyl Salicylate)4 and Its Protective Effect Against Streptozotocin-Induced Diabetes Mellitus in Rats

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Oxidative stress has been suggested as a potential contributor to the development of diabetic complications. In this study, we investigated the protective effect of a strong antioxidant copper complex against streptozotocin (STZ)-induced diabetes in animals. Out of four copper complexes used, copper(II) (3,5-diisopropyl salicylate)4 (Cu(II)DIPS) was found to be the most potent antioxidant–copper complex. Pretreatment with Cu(II)DIPS (5 mg/kg) twice a week prior to the injection of streptozotocin (50 mg/kg) has reduced the level of hyperglycemia by 34 % and the mortality rate by 29 %. Injection of the same dosage of the ligand 3,5-diisopropyl salicylate has no effect on streptozotocin-induced hyperglycemia. The same copper complex has neither hypoglycemic activity when injected in normal rats nor antidiabetic activity when injected in STZ-induced diabetic rats. The protective effect of Cu(II)DIPS could be related to its strong antioxidant activity compared to other copper complexes median effective concentration (MEC) = 23.84 μg/ml and to Trolox MEC = 29.30 μg/ml. In addition, it reduced serum 8-hydroxy-2′-deoxyguanosine, a biomarker of oxidative DNA damage, by 29 %. This effect may explain why it was not effective against diabetic rats, when β Langerhans cells were already destroyed. Similar protective activities were reported by other antioxidants like Trolox.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Anderson D, Yu TW, Wright J, Ioannides C (1998) An examination of DNA strand breakage in the comet assay and antioxidant capacity in diabetic patients. Mutat Res 398:151–161

    Article  PubMed  CAS  Google Scholar 

  2. Collins AR, Raslova K, Somorovska M, Petrovska H, Ondrusova A, Vohnout B, Fabry R, Dusinska M (1998) DNA damage in diabetes: correlation with a clinical marker. Free Radic Biol Med 25:373–377

    Article  PubMed  CAS  Google Scholar 

  3. Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L (2001) The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association, and the German Diabetes Society. Diabetes Metab Res Rev 17:189–212

    Article  PubMed  CAS  Google Scholar 

  4. Hansen PA, Holloszy JO, Heinecke JW, Leeuwenburgh CH (1999) Oxidized amino acids in the urine of aging rats: potential markers for assessing oxidative stress in vivo. Am J Physiol 276:128–135

    Google Scholar 

  5. Ziouzenkova O, Sevanian A, Abuja PM, Ramos P (1998) Copper can promote oxidation of LDL by markedly different mechanisms. Free Radical Biol Med 24:607–623

    Article  CAS  Google Scholar 

  6. Marnett LJ (2000) Oxyradicals and DNA damage. Carcinogenesis 21:361–370

    Article  PubMed  CAS  Google Scholar 

  7. Vozar J (1998) Diabetes mellitus, 1st edn. Slovak Academic, Bratislava, pp 60–140

    Google Scholar 

  8. Fielden EM, Rotilio G (1984) The structure and mechanism of Cu/Zn-superoxide dismutase. In: Lontie R (ed) Copper proteins and copper enzymes II. CRC, Boca Raton, p 55

    Google Scholar 

  9. Gillery P, Monboisse JC, Maquart FX, Borel JP (1988) Glycation of proteins as a source of superoxide. Diabetes & Metab 14:25–30

    CAS  Google Scholar 

  10. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  PubMed  CAS  Google Scholar 

  11. Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamaru K, Hirashima Y et al (2003) Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells. Biochem Biophys Res Commun 300:216–222

    Article  PubMed  CAS  Google Scholar 

  12. Sena CM, Nunes E, Louro T, Proenca T, Seica RM (2007) Endothelial dysfunction in type 2 diabetes: effect of antioxidants. Rev Port Cardiol 26(6):609–619

    PubMed  Google Scholar 

  13. Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2003) Perspectives in diabetes: are oxidative stress activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 52:1–8

    Article  PubMed  CAS  Google Scholar 

  14. Baynes JW, Thorpe SR (1999) Perspectives in diabetes. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48(1):1–9

    Article  PubMed  CAS  Google Scholar 

  15. Pitozzi V, Giovannelli L, Bardini G, Rotella CM, Dolara P (2003) Oxidative DNA damage in peripheral blood cells in type 2 diabetes mellitus: higher vulnerability of polymorphonuclear leukocytes. Mutat Res 529:129–133

    Article  PubMed  CAS  Google Scholar 

  16. Vanco J, Marek J, Trávnícek Z, Racanská E, Muselík J, Svajlenová O (2007) Synthesis, structural characterization, antiradical and antidiabetic activities of copper(II) and zinc(II) Schiff base complexes derived from salicylaldehyde and beta-alanine. J Inorg Biochem 102(4):595–605

    Article  PubMed  Google Scholar 

  17. Brewer GJ, Dick R, Zeng C, Hou G (2006) The use of tetrathiomolybdate in treating fibrotic, inflammatory, and autoimmune diseases, including the non-obese diabetic mouse model. J Inorg Biochem 100:927–930

    Article  PubMed  CAS  Google Scholar 

  18. Gong D, Lu J, Chen X, Reddy S, Crosman DL, Glyn-Jones S, Choong YS, Kennedy J, Barry B, Zhang S, Chan YK, Roggiero K, Phillips AR, Cooper GJ (2008) A copper (II)-selective chelator ameliorates diabetes-evoked renal fibrosis and albuminuria, and suppresses pathogenic TGF-beta activation in the kidneys of rats used as a model of diabetes. Diabetologia 51:1741–1751

    Article  PubMed  CAS  Google Scholar 

  19. Basaki M, Saeb M, Nazifi S, Shamsaei HA (2012) Zinc, copper, iron, and chromium concentrations in young patients with type 2 diabetes mellitus. Biol. Trace Elem Res 148:161–164

    Article  CAS  Google Scholar 

  20. Tanaka A, Kaneto H, Miyatsuka T, Yamamoto K, Yoshiuchi K, Yamasaki Y, Shimomura I, Matsuoka T, Matsuhisa M (2009) Role of copper in the pathogenesis of type 2 diabetes. Endocr J 56(5):699–706

    Article  PubMed  CAS  Google Scholar 

  21. Viossat B, Daran JC, Savouret G, Morgant G, Greenaway FT, Dung NH, Pham-Tran VA, Sorenson JR (2003) Low-temperature (180 K) crystal structure, electron paramagnetic resonance spectroscopy, and propitious anticonvulsant activities of CuII2(aspirinate)4(DMF)2 and other CuII2(aspirinate)4 chelates. J Inorg Biochem 96(2–3):375–385

    Article  PubMed  CAS  Google Scholar 

  22. Abdul-Ghani AS, Abu-Hijleh AL, Qazzaz M, Muhaisen A, Ghani RA (2005) Stimulated release of exogenous GABA and glutamate from cerebral cortical synaptosomes and brain slices by bis(acetato)tetrakis(imidazole) copper(II) complex. Biol Trace Elem Res 108(1–3):205–14

    Article  PubMed  CAS  Google Scholar 

  23. Oberley LW, Leuthauser SW, Pasternack RF, Oberley TD, Schutt L, Sorenson JR (1984) Anticancer activity of metal compounds with superoxide dismutase activity. Agents Actions 15(5–6):535–8

    Article  PubMed  CAS  Google Scholar 

  24. Kovala-Demertzi D, Hadjipavlou-Litina D, Staninska M, Primikiri A, Kotoglou C, Demertzis MA (2009) Anti-oxidant, in vitro, in vivo anti-inflammatory activity and antiproliferative activity of mefenamic acid and its metal complexes with manganese(II), cobalt(II), nickel(II), copper(II) and zinc(II). J Enzyme Inhib Med Chem 24(3):742–52

    Article  PubMed  CAS  Google Scholar 

  25. Al-Amiery AA (2011) Antimicrobial and antioxidant activities of new metal complexes derived from (E)-3-((5-phenyl-1,3,4-oxadiazol-2-ylimino)methyl)naphthalen-2-ol. Med Chem Res 21:3204–3213

    Article  Google Scholar 

  26. Tuorkey MJ, Abdul-Aziz KK (2009) A pioneer study on the anti-ulcer activities of copper nicotinate complex [CuCl (HNA)2] in experimental gastric ulcer induced by aspirin-pylorus [corrected] ligation model (Shay model). Biomed Pharmacother 63(3):194–201

    Article  PubMed  CAS  Google Scholar 

  27. Gandy SE, Buse MG, Sorenson JR, Crouch RK (1983) Attenuation of streptozotocin diabetes with superoxide dismutase-like copper(II)(3,5-diisopropylsalicylate)2 in the rat. Diabetologia 24(6):437–40

    Article  PubMed  CAS  Google Scholar 

  28. Abdul-Ghani AS, Abu-Hijleh AL, Nahas N, Amin R (1996) Hypoglycemic effect of copper(II) acetate imidazole complexes. Biol Trace Elem Res 54(2):143–51

    Article  PubMed  CAS  Google Scholar 

  29. Yasumatsu N, Yoshikawa Y, Adachi Y, Sakurai H (2007) Antidiabetic copper(II)-picolinate: impact of the first transition metal in the metallopicolinate complexes. Bioorg Med Chem 15(14):4917–22

    Article  PubMed  CAS  Google Scholar 

  30. Duncan C, White AR (2012) Copper complexes as therapeutic agents. Metallomics 4(2):127–138

    Article  PubMed  CAS  Google Scholar 

  31. Booth BL, Pitters E, Mayer B, Sorenson JR (1999) Down-regulation of porcine heart diaphorase reactivity by trimanganese hexakis(3,5-diisopropylsalicylate), Mn(3)(3,5-DIPS)6, and down-regulation of nitric oxide synthase reactivity by Mn(3)(3,5-DIPS)(6) and Cu(II)(2)(3,5-DIPS)(4). Met Based Drugs 6(2):111–20

    Article  PubMed  CAS  Google Scholar 

  32. Sorenson JR, Soderberg LS, Baker ML, Barnett JB, Chang LW, Salari H, Willingham WM (1990) Radiation recovery agents: Cu(II), Mn(II), Zn(II), or Fe(III) and 3,5-diisopropylsalicylate complexes facilitate recovery from ionizing radiation induced radical mediated tissue damage. Adv Exp Med Biol 264:69–77

    Article  PubMed  CAS  Google Scholar 

  33. Abdul-Ghani AS, Abu-Hijleh AL, Qazzaz M (2004) Effect of bis(acetato)tetrakis(imidazole) copper(II) in delaying the onset and reducing the mortality rate of strychnine- and thiosemicarbazide-induced convulsions. Biol Trace Elem Res 101(1):87–95

    Article  PubMed  CAS  Google Scholar 

  34. Glazer AN (1990) Phycoerythrin: fluorescence-based assay for reactive oxygen species. Methods Enzymol 186:161–168

    Article  PubMed  CAS  Google Scholar 

  35. Cao G, Alessio HM, Cutler RG (1993) Oxygen-radical absorbance capacity assay for antioxidants. Free Radic Biol Med 14:303–311

    Article  PubMed  CAS  Google Scholar 

  36. Prior RL, Cao G (1999) In vivo total antioxidant capacity comparison of different analytical methods. Free Radic Biol Med 27(11/12):1173–1181

    Article  PubMed  CAS  Google Scholar 

  37. Cattley RC, Glover SE (1993) Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization. Carcinogenesis 14(12):2495–2499

    Article  PubMed  CAS  Google Scholar 

  38. Alam ZI, Jenner A, Danial SE, Lees AJ, Cairn SN, Marsden CD, Jenner P, Halliwell B (1997) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 69:1196–1203

    Article  PubMed  CAS  Google Scholar 

  39. Lezza AM, Mecocci P, Cormio A, Beal MF, Cherubini A, Cantatore P, Senin U, Gadaleta MN (1999) Mitochondrial DNA 4977 bp deletion and 8-OHdG levels correlate in the brain of aged subjects but not Alzheimer's disease patients. FASEB J 13:1083–1088

    PubMed  CAS  Google Scholar 

  40. Chiou CC, Chang PY, Chan EC, Wu TL, Tsao KC, Wu JT (2003) Urinary 8-hydroxydeoxyguanosine and its analogs as DNA marker of oxidative stress: development of an ELISA and measurement in both bladder and prostate cancers. Clin Chim Acta 334:87–94

    Article  PubMed  CAS  Google Scholar 

  41. Yamamoto BK, Zhu W (1998) The effects of methamphetamine on the production of free radicals and oxidative stress. J Pharmacol Exp Ther 287:107–114

    PubMed  CAS  Google Scholar 

  42. Vanco J, Svajlenova O, Racanski E, Muselik J, Valentova J (2004) Antiradical activity of different copper(II) Schiff base complexes and their effect on alloxan-induced diabetes. J Trace Elem Med Biol 18:155–161

    Article  PubMed  CAS  Google Scholar 

  43. Lu YX, Zhang Q, Li J, Sun YY, Wang LY, Cheng WM, Xiang-Yangz H (2010) Antidiabetic effects of total flavonoids from Litsea coreanaleve on fat-fed, streptozotocin-induced type 2 diabetic rats. Am J Chin Med 38(4):713–725

    Article  PubMed  CAS  Google Scholar 

  44. Kazi TG, Afridi HI, Kazi N, Jamali MK, Arain MB, Jalbani N, Kandhro GA (2008) Copper, chromium, manganese, iron, nickel and zinc levels in biological samples of diabetes mellitus patients. Biol Trac Elem Res 122:1–18

    Article  CAS  Google Scholar 

  45. Zhao C, Wang H, Zhang J, Feng L (2008) Correlations of trace elements, glucose and body compositions in type 2 diabetics. Wei Shengb Yan Jiu 37:600–601

    CAS  Google Scholar 

  46. Pieper GM, Jordan M, Donglinger LA, Adam MB, Roza AM (1995) Peroxidative stress in diabetic blood vessels. Diabetes 44:884–889

    Article  PubMed  CAS  Google Scholar 

  47. Cunningham JJ (1998) Micronutrients as nutraceutical interventions in diabetes mellitus. J Am Coll Nutr 17:7–10

    Article  PubMed  CAS  Google Scholar 

  48. Duman BS, Ozturk M, Yilmazer S, Hatemi H (2003) Thiols, malonaldehyde and total antioxidant status in the Turkish patients with type 2 diabetes mellitus. Tohoku J Exp Med 201:147–155

    Article  PubMed  CAS  Google Scholar 

  49. Fernando GR, Martha RM (2005) Complementary therapies for diabetes: the case for chromium, magnesium and antioxidants. Arch Med Res 36:250–257

    Article  Google Scholar 

  50. Abou-Seif MA, Youssef A (2004) Evaluation of some biochemical changes in diabetic patients. Clin Chim Acta 346:161–170

    Article  PubMed  CAS  Google Scholar 

  51. Hunt JV, Smith CC, Wolff SP (1990) Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose. Diabetes 39:1420–1424

    Article  PubMed  CAS  Google Scholar 

  52. Masad A, Hayes L, Tabner BJ, Turnbull S, Cooper LJ, Fullwood NJ, German MJ, Kametani F, El-Agnaf OM, Allsop D (2007) Copper-mediated formation of hydrogen peroxide from the amylin peptide: a novel mechanism for degeneration of islet cells in type-2 diabetes mellitus? FEBS Lett 581:3489–3493

    Article  PubMed  CAS  Google Scholar 

  53. Sitasawad M, Deshpande M, Katdare S, Tirth S, Parab P (2001) Beneficial effect of supplementation with copper sulfate on STZ-diabetic mice (IDDM). Diabetes Res Clin Pract 52:77–84

    Article  PubMed  CAS  Google Scholar 

  54. Wiernsperger NF (2003) Oxidative stress as a therapeutic target in diabetes. Revisiting the controversy. Diabetes Metab. (6): 579–585.

  55. Stetina R, Varvarovaka J, Rusavy Z, Pomahacova R, Racek J, Lacigova S, Trefil L, Siala K, Stozicky F (2006) Oxidative stress, DNA damage and DNA repair capacity in children with type 1 diabetes mellitus. Toxicol Lett 164(Supp l):S1–134

    Google Scholar 

  56. Shigenaga MK, Ames BN (1991) Assay for 8-hydroxy-2′-deoxyguanosine: a biomarker of in vivo oxidative DNA damage. Free Radic Biol Med 10:211–216

    Article  PubMed  CAS  Google Scholar 

  57. Fairbairn DW, Olive PL, O'Neill KL (1995) The comet assay: a comprehensive review. Mutat Res 339:37–59

    Article  PubMed  CAS  Google Scholar 

  58. Imaeda A, Kaneko T, Aoki T, Kondo Y, Nagase H (2002) DNA damage and the effect of antioxidants in streptozotocin-treated mice. Food Chem Toxicol 40(7):979–987

    Article  PubMed  CAS  Google Scholar 

  59. Kraynak AR, Storer RD, Jensen RD, Kloss MW, Soper KA, Clair JH, Deluca JG, Nichols WW, Eydelloth RS (1995) Extent and persistence of streptozotocin-induced DNA damage and cell proliferation in rat kidney as determined by in vitro alkaline elution and BrdUrd labelling assays. Toxicol Appl Pharmacol 135:279–286

    Article  PubMed  CAS  Google Scholar 

  60. Dandona P, Thusu K, Cook S, Snyder B, Makowski J, Armstrong D, Nicotera T (1996) Oxidative damage to DNA in diabetes mellitus. Lancet 347:444–445

    Article  PubMed  CAS  Google Scholar 

  61. Leinonen J, Lehtimaki T, Toyokuni S et al (1996) New biomarkers evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus. FEBS Lett 417:150–152

    Article  Google Scholar 

  62. Hinokio Y, Suzuki S, Hirai M, Chiba M, Hirai A, Toyota T (1999) Oxidative DNA damage in diabetes mellitus: its association with diabetic complications. Diabetologia 42:995–998

    Article  PubMed  CAS  Google Scholar 

  63. Soon YY, Tan BKH (2002) Evaluation of the hypoglycemic and anti-oxidant activities of Morinda officinalis in streptozotocin-induced diabetic rats. Singap Med J 43(2):77–85

    CAS  Google Scholar 

  64. Heikkila RE, Cabbat FS, Cohen G (1976) In vivo inhibition of superoxide dismutase in mice by diethyldithiocarbamate. J Biol Chem 251:2182–2185

    PubMed  CAS  Google Scholar 

  65. Crouch RK, Gandy SE, Kimsey G, Galbraith RA, Galbraith GMP, Buse MG (1981) The inhibition of islet superoxide dismutase by diabetogenic drugs. Diabetes 30:235–241

    PubMed  CAS  Google Scholar 

  66. Robbins MJ, Sharp RA, Slonim AE, Burr IM (1980) Protection against streptozotocin diabetes by superoxide dismutase. Diabetologia 18:55–58

    Article  PubMed  CAS  Google Scholar 

  67. Gandy S, Buse M, Crouch R (1982) Protective role of superoxide dismutase against diabetogenic drugs. J Clin Invest 70:650–658

    Article  PubMed  CAS  Google Scholar 

  68. Lengfelder E, Weser U (1981) Superoxide dismutase by low molecular weight Cu-complexes. Bull Eur Physiopath Resp 17(Supp l):73–80

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Nursing and Allied Health Professions, Birzeit University, Birzeit, Palestine

    Munir Qazzaz

  2. Biochemistry Department, Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine

    Rula Abdul-Ghani

  3. Biology and Biochemistry Department, Faculty of Science, Birzeit University, Birzeit, Palestine

    Munther Metani & Rateb Husein

  4. Chemistry Department, Faculty of Science, Birzeit University, Birzeit, Palestine

    Abdul-Latif Abu-Hijleh

  5. Physiology & Pharmacology Department, Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine

    Abdul-Salam Abdul-Ghani

Authors
  1. Munir Qazzaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rula Abdul-Ghani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Munther Metani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rateb Husein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdul-Latif Abu-Hijleh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Abdul-Salam Abdul-Ghani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Munir Qazzaz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qazzaz, M., Abdul-Ghani, R., Metani, M. et al. The Antioxidant Activity of Copper(II) (3,5-Diisopropyl Salicylate)4 and Its Protective Effect Against Streptozotocin-Induced Diabetes Mellitus in Rats. Biol Trace Elem Res 154, 88–96 (2013). https://doi.org/10.1007/s12011-013-9697-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-013-9697-5

Keywords

Search

Navigation