Journal of Physiology and Biochemistry

, Volume 69, Issue 4, pp 761–778 | Cite as

Adverse cardiac responses to alpha-lipoic acid in a rat-diabetic model: possible mechanisms?

  • Nouf M. AL-Rasheed
  • Nawal M. Al-Rasheed
  • Hala A. Attia
  • Iman H. HasanEmail author
  • Maha Al-Amin
  • Hanaa Al-Ajmi
  • Raeesa A. Mohamad
Original Paper


Alpha-lipoic acid (ALA) is widely used as an antioxidant for the treatment of diabetes and its complications; however, the pro-oxidant potential of ALA has recently been reported. This study was designed to investigate whether ALA supplementation could have pro-oxidant effects on cardiac tissues in normal and diabetic rats. Diabetes was induced by a single dose of streptozotocin (STZ; 55 mg/kg (intraperitoneal). Diabetic and normal rats were treated with ALA (100 mg kg−1 day−1) for 45 days. ALA supplementation resulted in oxidative protein damage as evident by significant reduction in the cardiac levels of protein thiol in ALA-treated normal rats (P < 0.01) together with a significant elevation (P < 0.001) in the plasma levels of advanced oxidation protein products in ALA-treated normal rats and in ALA + STZ-diabetic rats compared with the normal control rats. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has emerged as the major source of superoxide anion and enhanced oxidative damage in heart failure. ALA supplementation increased the myocardial immunoreactivity of p47phox subunit of NADPH oxidase in both normal nondiabetic and diabetic rats reflecting its pro-oxidant effect. Data showed that ALA supplementation failed to prevent cardiac complications in diabetic rats and led to cardiac toxicity in normal rats as indicated by pathological changes (cellular infiltration, fibrosis, and degeneration) and by the elevation of serum cardiac biomarkers compared with normal controls. The pro-oxidant effects of ALA suggest that careful selection of appropriate doses of ALA in reactive oxygen species-related diseases are critical.


Alpha-lipoic acid Diabetic complication Protein thiol Advanced oxidation protein product Vascular endothelial growth factor 



This research project was supported by a grant from the “Research Centre of the Centre for Female Scientific and Medical Colleges,” Deanship of Scientific Research, King Saud University. In addition, this work was partially supported by Global Research Network for Medicinal Plants (GRNMP) and King Saud University.

Conflict of interest statement

The authors declare no conflict of interest. The sponsor’s studies mainly supported the work financially and had no involvement in the study design, collection, analysis and interpretation of data, writing of the manuscript, and the decision to submit the manuscript for publication.


  1. 1.
    Abaci A, Oguzhan A, Kahraman S, Eryol NK, Unal S, Arinc H, Ergin A (1999) Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 99:2239–2242PubMedCrossRefGoogle Scholar
  2. 2.
    Aebi H (1974) Catalase. In: Bergmayer HU (ed.) Methods of enzymatic analysis, 2nd edn. Academic, New York. pp. 673–684Google Scholar
  3. 3.
    Alderman C, Shah S, Foreman JC, Chain BM, Katz DR (2002) The role of advanced oxidation protein products in regulation of dendritic cell function. Free Radic Biol Med 32:377–385PubMedCrossRefGoogle Scholar
  4. 4.
    Aoyama S, Okimura Y, Fujita H, Sato EF, Umegaki T, Abe K, Inoue M, Utsumi K, Sasaki J (2006) Stimulation of membrane permeability transition by alpha-lipoic acid and its biochemical characteristics. Physiol Chem Phys Med NMR 38(1):1–20PubMedGoogle Scholar
  5. 5.
    Balkis Budin S, Othman F, Louis SR, Abu Bakar M, Radzi M, Osman K, Das S, Mohamed J, Rom J (2009) Effect of alpha lipoic acid on oxidative stress and vascular wall of diabetic rats. Morphol Embryol 50(1):23–30Google Scholar
  6. 6.
    Bhatti F, Mankhey RW, Asico L, Quinn MT, Welch WJ, Maric C (2005) Mechanisms of antioxidant and pro-oxidant effects of alpha-lipoic acid in the diabetic and nondiabetic kidney. Kidney Int 67(4):1371–1380PubMedCrossRefGoogle Scholar
  7. 7.
    Biewenga GP, Haenen GR, Bast A (1997) The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 29:315–331PubMedCrossRefGoogle Scholar
  8. 8.
    Borcea V, Nourooz-Zadeh J, Wolff SP, Klevesath M, Hofmann M, Urich H, Wahl P (1999) α-Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria. Free Radic Biol Med 26:1495–1500PubMedCrossRefGoogle Scholar
  9. 9.
    Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH (1998) Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med 24(6):1023–1039PubMedCrossRefGoogle Scholar
  10. 10.
    Cai L, Kang YJ (2001) Oxidative stress and diabetic cardiomyopathy: a brief review. Cardiovasc Toxicol 1:181–193PubMedCrossRefGoogle Scholar
  11. 11.
    Cakatay U (2006) Pro-oxidant actions of α-lipoic acid and dihydrolipoic acid. Medical Hypotheses 66(1):110–117PubMedCrossRefGoogle Scholar
  12. 12.
    Cakatay U, Kayali R (2005) Plasma protein oxidation in aging rats after alpha-lipoic acid administration. Biogerontology 6(2):87–93PubMedCrossRefGoogle Scholar
  13. 13.
    Cakatay U, Kayali R, Sivas A, Tekeli F (2005) Prooxidant activities of alpha-lipoic acid on oxidative protein damage in the aging rat heart muscle. Arch Gerontol Geriatr 40(3):231–240PubMedCrossRefGoogle Scholar
  14. 14.
    Ceriello A (2003) New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 26:1589–1596PubMedCrossRefGoogle Scholar
  15. 15.
    Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, Suzuma K, Bowling NL, Vlahos CJ, Aiello LP, King GL (2002) Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation 105:373–379PubMedCrossRefGoogle Scholar
  16. 16.
    Coleman MD, Walker CL (2000) Effects of the antioxidants α-lipoic acid and α-tocopherol on xenobiotic-mediated methaemoglobin formation in human diabetic and non-diabetic erythrocytes in vitro. Env Tox Pharmacol 8:127–132CrossRefGoogle Scholar
  17. 17.
    Coleman MD, Williams C, Haenen GR. (2006). Effects of lipoic acid and dihydrolipoic acid on 4-aminophenol-mediated erythrocytic toxicity in vitro. Basic Clin Pharmacol Toxicol 99(3):225–229Google Scholar
  18. 18.
    Cremer DR, Rabeler R, Roberts A, Lynch B (2006) Safety evaluation of alpha-lipoic acid (ALA). Regul Toxicol Pharmacol 46(1):29–41PubMedCrossRefGoogle Scholar
  19. 19.
    Da Ros R, Assaloni R, Ceriello A (2004) Antioxidant therapy in diabetic complications: what is new? Curr Vasc Pharmacol 2:335–341PubMedCrossRefGoogle Scholar
  20. 20.
    De La Fuente M, Miquel J, Catalan MP, Victor VM, Guayerbas N (2002) The amount of thiolic antioxidant ingestion needed to improve several immune functions is higher in aged than in adult mice. Free Radic Res 36:119–126CrossRefGoogle Scholar
  21. 21.
    Dicter N, Madar Z, Tirosh O (2002) Alpha-lipoic acid inhibits glycogen synthesis in rat soleus muscle via its oxidative activity and the uncoupling of mitochondria. J Nutr 132(10):3001–3006PubMedGoogle Scholar
  22. 22.
    Dieckmann A, Kriebel M, Andriambeloson E, Ziegler D, Elmlinger M (2012) Treatment with Actovegin® improves sensory nerve function and pathology in streptozotocin-diabetic rats via mechanisms involving inhibition of PARP activation. Exp Clin Endocrinol Diabetes 120(3):132–138PubMedCrossRefGoogle Scholar
  23. 23.
    Duncan JG, Fong JL, Medeiros DM, Finck BN, Kelly DP (2007) Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation 115(7):909–917PubMedCrossRefGoogle Scholar
  24. 24.
    Estrada DE, Ewart HS, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H, Klip A (1996) Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes 45:1798–1804PubMedCrossRefGoogle Scholar
  25. 25.
    Feillet-Coudray C, Rock E, Coudray C, Grzelkowska K, Azais-Braesco V, Dardevet D, Mazur A (1999) Lipid peroxidation and antioxidant status in experimental diabetes. Clin Chim Acta 284(1):31–43PubMedCrossRefGoogle Scholar
  26. 26.
    Ghibu S, Delemasure S, Richard C, Guilland JC, Martin L, Gambert S, Rochette L, Vergely C (2012) General oxidative stress during doxorubicin-induced cardiotoxicity in rats: Absence of cardioprotection and low antioxidant efficiency of alpha-lipoic acid 94(4):932–939Google Scholar
  27. 27.
    Golbidi S, Ebadi SA, Laher I (2011) Antioxidants in the treatment of diabetes. Curr Diabetes Rev 7(2):106–125PubMedCrossRefGoogle Scholar
  28. 28.
    Gorąca A, Huk-Kolega H, Piechota A, Kleniewska P, Ciejka E, Skibska B (2011) Lipoic acid - biological activity and therapeutic potential. Pharmacol Rep 63(4):849–858PubMedGoogle Scholar
  29. 29.
    Gorraca A, Pilechota A, Huk-kolega H (2009) Effect of alpha-lipoic acid on LPS-induced oxidative stress in the heart. J Physiol Pharmacol 60(1):61–68Google Scholar
  30. 30.
    Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86:494–501PubMedCrossRefGoogle Scholar
  31. 31.
    Han D, Handelman G, Marcocci L et al (1997) Lipoic acid increases de novo synthesis of cellular glutathione by improving cysteine utilization. Biofactors 6:321–338PubMedCrossRefGoogle Scholar
  32. 32.
    Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, Augustin HJ, Dietze GJ (1995) Enhancement of glucose disposal in patients with type 2 diabetes by α-lipoic acid. Arzneimittelforschung 45:872–874PubMedGoogle Scholar
  33. 33.
    Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, Henriksen EJ (1996) The antioxidant α-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Diabetes 45:1024–1029PubMedCrossRefGoogle Scholar
  34. 34.
    Johnsen-Soriano S, Garcia-Pous M, Arnal E, Sancho-Tello M, Garcia-Delpech S, Miranda M, Bosch-Morell F, Diaz-lopis M, Navea A, Romero FJ (2008) Early lipoic acid intake protects retina of diabetic mice. Free Radic Res 42(7):613–617PubMedCrossRefGoogle Scholar
  35. 35.
    Kalousová M, Skrha J, Zima T (2002) Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus. Physiol Res 51(6):597–604PubMedGoogle Scholar
  36. 36.
    Kandeil MA, Amin KA, Hassanin KA, Ali KM, Mohammed ET (2011) Role of lipoic acid on insulin resistance and leptin in experimentally diabetic rats. J Diabetes Complications 25(1):31–38PubMedCrossRefGoogle Scholar
  37. 37.
    Kayali R, Cakatay U, Akçay T, Altuğ T (2006) Effect of alpha-lipoic acid supplementation on markers of protein oxidation in post-mitotic tissues of ageing rat. Cell Biochem Funct 24(1):79–85PubMedCrossRefGoogle Scholar
  38. 38.
    Kayali R, Cakatay U, Kiziler AR, Aydemir B (2007) Effect of alpha-lipoic acid supplementation on trace element levels in serum and in postmitotic tissue in aged rats. Med Chem 3(3):297–300PubMedCrossRefGoogle Scholar
  39. 39.
    Kim HS, Kim HJ, Park KG, Kim YN, Kwon TK, Park JY, Lee KU, Kim JG, Lee IK (2007) Lipoic acid inhibits matrix metalloproteinase-9 expression by inhibiting NF-κB transcriptional activity. Exp Mol Med 39:106–113PubMedCrossRefGoogle Scholar
  40. 40.
    Kocak G, Aktan F, Canbolat O, Ozogul C, Elbeg S, Yildizoglu-Ari N, Karasu C, ADIC Study Group—Antioxidants in Diabetes-Induced Complications (2000) Alpha-lipoic acid treatment ameliorates metabolic parameters, blood pressure, vascular reactivity and morphology of vessels already damaged by streptozotocin-diabetes. Diabetes Nutr Metab 13(6):308–318PubMedGoogle Scholar
  41. 41.
    Koh EH, Lee WJ, Lee SA, Kim EH, Cho EH, Jeong E, Kim DW, Kim MS, Park JY, Park KG, Lee HJ, Lee IK, Lim S, Jang HC, Lee KH, Lee KU (2011) Effects of alpha-lipoic acid on body weight in obese subjects. Am J Med 124(85):e1–e8PubMedGoogle Scholar
  42. 42.
    Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, Tritschler HJ, Cobelli C, Usadel KH (1999) α-lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care 22:280–287PubMedCrossRefGoogle Scholar
  43. 43.
    Lappalainen Z, Lappalainen J, Laaksonen DE, Oksala KJ, Khanna S, Sen CK, Atalay M (2010) Acute exercise and thioredoxin-1 in rat brain, and alpha-lipoic acid and thioredoxin-interacting protein response, in diabetes. Int J Sport Nutr Exerc Metab 20(3):206–215PubMedGoogle Scholar
  44. 44.
    Lee SG, Lee CG, Yun IH, Hur DY, Yang JW, Kim HW (2012) Effect of lipoic acid on expression of angiogenic factors in diabetic rat retina. Clin Experiment Ophthalmol 40(1):47–57CrossRefGoogle Scholar
  45. 45.
    Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW (2000) Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med 342:626–633PubMedCrossRefGoogle Scholar
  46. 46.
    Lee JE, Yi CO, Jeon BT, Shin HJ, Kim SK, Jung TS, Choi JY, Roh GS (2012) Alpha-lipoic acid attenuates cardiac fibrosis in Otsuka Long-Evans Tokushima fatty rats. Cardiovasc Diabetol 11(1):111PubMedCrossRefGoogle Scholar
  47. 47.
    Li JM, Gall NP, Grieve DJ, Chen M, Shah AM (2002) Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. Hypertension 40:477–484PubMedCrossRefGoogle Scholar
  48. 48.
    Li CJ, Zhang QM, Li MZ, Zhang JY, Yu P, Yu DM (2009) Attenuation of myocardial apoptosis by alpha-lipoic acid through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy. Chin Med J [Engl] 122(21):2580–2586Google Scholar
  49. 49.
    Lodge JK, Traber MG, Packer L (1998) Thiol chelation of Cu2+ by dihydrolipoic acid prevents human low density lipoprotein peroxidation. Free RadicBiol Med 25:287–297CrossRefGoogle Scholar
  50. 50.
    Marangon K, Devaraj S, Tirosh O, Packer L, Jialal I (1999) Comparison of the effect of α-lipoic acid and α-tocopherol supplementation on measures of oxidative stress. Free Radic Biol Med 27:1114–1121PubMedCrossRefGoogle Scholar
  51. 51.
    Maritim AC, Sanders RA, Watkins JB (2003) Effects of alpha-lipoic acid on biomarkers of oxidative stress in streptozotocin-induced diabetic rats. J Nutr Biochem 14(5):288–94PubMedCrossRefGoogle Scholar
  52. 52.
    Moini H, Packer L, Saris NEL (2002) Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol 182(1):84–90PubMedCrossRefGoogle Scholar
  53. 53.
    Moini H, Tirosh O, Park YC, Cho KJ, Packer L (2002) R-α-lipoic acid action on cell redox status, the insulin receptor, and glucose uptake in 3T3–L1 adipocytes. Arch Biochem Biophys 397:384–91PubMedCrossRefGoogle Scholar
  54. 54.
    Morkunaite S, Kruglov AG, Teplova VV, Stolze K, Gille L, Nohl H, Saris NE (2003) Reactive oxygen species are involved in the stimulation of the mitochondrial permeability transition by dihydrolipoate. Biochem Pharmacol 65(1):43–49CrossRefGoogle Scholar
  55. 55.
    Morkunaite S, Teplova VV, Saris NE (2000) Mechanism of dihydrolipoate stimulation of the mitochondrial permeability transition: effect of different respiratory substrates. IUBMB Life 49(3):211–216PubMedGoogle Scholar
  56. 56.
    Moron MS, Depierre J, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochem Biophys Acta 582:67–78PubMedCrossRefGoogle Scholar
  57. 57.
    Murdoch CE, Zhang M, Cave AC, Shah AM (2006) NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure. Cardiovasc Res 71:208–215PubMedCrossRefGoogle Scholar
  58. 58.
    Obrosova G, Fathallah L, Liu E, Nourooz-Zadeh J (2003) Early oxidative stress in the diabetic kidney: effect of dl-α-lipoic acid. Free Radic Biol Med 34:186–195PubMedCrossRefGoogle Scholar
  59. 59.
    Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358PubMedCrossRefGoogle Scholar
  60. 60.
    Peng T, Lu X, Feng Q (2005) Pivotal role of gp91phox-containing NADH oxidase in lipopolysaccharide-induced tumor necrosis factor-alpha expression and myocardial depression. Circulation 111:1637–1644PubMedCrossRefGoogle Scholar
  61. 61.
    Petersen Shay K, Moreau RF, Smith EJ, Hagen TM (2008) Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity. IUBMB Life 60(6):362–367PubMedCrossRefGoogle Scholar
  62. 62.
    Pfanzagl B, Tribl F, Koller E, Möslinger T (2003) Homocysteine strongly enhances metal-catalyzed LDL oxidation in the presence of cystine and cysteine. Atherosclerosis 168(1):39–48PubMedCrossRefGoogle Scholar
  63. 63.
    Pierce RH, Campbell JS, Stephenson AB et al (2000) Disruption of redox homeostasis in tumor necrosis factor-induced apoptosis in a murine hepatocyte cell line. Am J Pathol 157:221–236PubMedCrossRefGoogle Scholar
  64. 64.
    Piotrowski P, Wierzbicka K, Smialek M (2001) Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia treated with antioxidants. Folia Neuropathol 39:147–154PubMedGoogle Scholar
  65. 65.
    Privratsky JR, Wold LE, Sowers JR, Quinn MT, Ren J (2003) AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase. Hypertension 42:206–212PubMedCrossRefGoogle Scholar
  66. 66.
    Rajesh M, Bátkai S, Kechrid M, Mukhopadhyay P, Lee WS, Horváth B, Holovac E, Cinar R, Liaudet L, Mackie K, Haskó G, Pacher P (2012) Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes 61(3):716–727PubMedCrossRefGoogle Scholar
  67. 67.
    Sahin M, Sagdic G, Elmas O, Akpinar D, Derin N, Aslan M, Agar A, Aliciguzel Y, Yargicoglu P (2006) Effect of chronic resistant stress and alpha-lipoic acid on lipid peroxidation and antioxidant enzyme activities in rat peripheral organs. Pharma Res 54:247–252CrossRefGoogle Scholar
  68. 68.
    Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205PubMedCrossRefGoogle Scholar
  69. 69.
    Sen CK, Sashwati R, Packer L (1999) Fas mediated apoptosis of human Jurkat T-cells: Intracellular events and potentiation by redox active alpha-lipoic acid. Cell Death Differ 6:481–491PubMedCrossRefGoogle Scholar
  70. 70.
    Shacter E (2000) Protein oxidative damage. Methods Enzymol 319:428–436PubMedCrossRefGoogle Scholar
  71. 71.
    Shen X, Zheng S, Thongboonkerd V, Xu M, Pierce WM Jr, Klein JB, Epstein PN (2004) Cardiac mitochondrial damage and biogenesis in a chronic model of type 1 diabetes. Am J Physiol Endocrinol Metab 287:E896–E905PubMedCrossRefGoogle Scholar
  72. 72.
    Shi XY, Hou FF, Niu HX, Wang GB, Xie D, Guo ZJ, Zhou ZM, Yang F, Tian JW, Zhang X (2008) Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. Endocrinology 149(4):1829–1839PubMedCrossRefGoogle Scholar
  73. 73.
    Stadtman ER, Levine RL (2003) Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino acids 25:207–218PubMedCrossRefGoogle Scholar
  74. 74.
    Tanguy S, de Leiris J, Besse S, Boucher F (2003) Ageing exacerbates the cardiotoxicity of hydrogen peroxide through the Fenton reaction in rats. Mech Ageing Dev 124(2):229–235PubMedCrossRefGoogle Scholar
  75. 75.
    Volchegorskii IA, Rassokhina LM, Miroshnichenko IY, Mester KM, Novoselov PN, Astakhova TV (2011) Effect of pro- and antioxidants on insulin sensitivity and glucose tolerance. Bull Exp Biol Med 150(3):327–332PubMedCrossRefGoogle Scholar
  76. 76.
    Wang Y, Li X, Guo Y, Chan L, Guan X (2010) Alpha-lipoic acid increases energy expenditure by enhancing adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling in the skeletal muscle of aged mice. Metabolism 59(7):967–976PubMedCrossRefGoogle Scholar
  77. 77.
    Wasan KM, Ng SP, Wong W, Rodrigues BB (1998) Streptozotocin- and alloxan-induced diabetes modifies total plasma and lipoprotein lipid concentration and composition without altering cholesteryl ester transfer activity. Pharmacol Toxicol 83(4):169–175PubMedCrossRefGoogle Scholar
  78. 78.
    Wendt MC, Daiber A, Kleschyov AL, Mulsch A, Sydow K, Schulz E, Chen K, Keaney JF Jr, Lassegue B, Walter U, Griendling KK, Munzel T (2005) Differential effects of diabetes on the expression of the gp91phox homologues nox1 and nox4. Free Radic Biol Med 39:381–391PubMedCrossRefGoogle Scholar
  79. 79.
    Wenzel U, Nickel A, Daniel H (2005) Alpha-lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2 −.−generation. Apoptosis 10(2):359–68PubMedCrossRefGoogle Scholar
  80. 80.
    Winiarska K, Malinska D, Szymanski K, Dudziak M, Bryla J (2008) Lipoic acid ameliorates oxidative stress and renal injury in alloxan diabetic rabbits. Biochimie 90(3):450–459PubMedCrossRefGoogle Scholar
  81. 81.
    Winterbourn CC (1993) Superoxide as an intracellular radical sink. Free Radic Biol Med 14:85–90PubMedCrossRefGoogle Scholar
  82. 82.
    Winterbourn CC, Peskin AV, Parsons-Mair HN (2002) Thiol oxidase activity of copper, zinc superoxide dismutase. J BiolChem 277:1906–1911Google Scholar
  83. 83.
    Witko-Sarsat V, Friedlander M, Capeillère-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49(5):1304–1313PubMedCrossRefGoogle Scholar
  84. 84.
    Wold LE, Ceylan-Isik AF, Ren J (2005) Oxidative stress and stress signaling: menace of diabetic cardiomyopathy. Acta Pharmacol Sin 26:908–917PubMedCrossRefGoogle Scholar
  85. 85.
    Yan W, Zhang H, Liu P, Wang H, Liu J, Gao C, Liu Y, Lian K, Yang L, Sun L, Guo Y, Zhang L, Dong L, Lau WB, Gao E, Gao F, Xiong L, Wang H, Qu Y, Tao L (2013) Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart. Basic Res Cardiol 108(3):329PubMedCrossRefGoogle Scholar
  86. 86.
    Yoon YS, Uchida S, Masuo O, Cejna M, Park JS, Gwon HC, Kirchmair R, Bahlman F, Walter D, Curry C, Hanley A, Isner JM, Losordo DW (2005) Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation 111:2073–2085PubMedCrossRefGoogle Scholar
  87. 87.
    Yu W, Wu J, Cai F, Xiang J, Zha W, Fan D, Guo SC (2012) Curcumin alleviates diabetic cardiomyopathy in experimental diabetic rats. PLoS One 7(12):e52013PubMedCrossRefGoogle Scholar
  88. 88.
    Zhang Y, Han P, Wu N, He B, Lu Y, Li S, Liu Y, Zhao S, Liu L, Li Y (2011) Amelioration of lipid abnormalities by α-lipoic acid through antioxidative and anti-inflammatory effects. Obesity 19(8):1647–1653PubMedCrossRefGoogle Scholar
  89. 89.
    Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, Samigullin R, Tritschler H, Munzel U, Maus J, Schütte K, Dyck PJ (2011) Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care 34(9):2054–2060PubMedCrossRefGoogle Scholar

Copyright information

© University of Navarra 2013

Authors and Affiliations

  • Nouf M. AL-Rasheed
    • 1
  • Nawal M. Al-Rasheed
    • 1
  • Hala A. Attia
    • 1
    • 2
  • Iman H. Hasan
    • 1
    Email author
  • Maha Al-Amin
    • 1
  • Hanaa Al-Ajmi
    • 1
  • Raeesa A. Mohamad
    • 3
  1. 1.Department of Pharmacology and Toxicology, College of PharmacyKing Saud UniversityRiyadhKingdom of Saudi Arabia
  2. 2.Department of Biochemistry, Faculty of PharmacyMansoura UniversityMansouraEgypt
  3. 3.Department of Anatomy, College of MedicineKing Saud UniversityRiyadhKingdom of Saudi Arabia

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