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Planta Med 2013; 79(09): 744-752
DOI: 10.1055/s-0032-1328588
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Salvia miltiorrhiza (Danshen) Injection Ameliorates Iron Overload-Induced Cardiac Damage in Mice

Jian-ping Zhang   *
1   Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
,
Yuan-yuan Zhang   *
1   Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
,
Ying Zhang
1   Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
,
Yong-gang Gao
1   Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
,
Juan-juan Ma
1   Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
,
Na Wang
1   Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
,
Jiang-yan Wang
2   Department of Biochemistry, Bethune Military Medical College, Shijiazhuang, Hebei, P. R. China
,
Yun Xie
1   Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
,
Feng-hua Zhang
3   Department of Diagnostics, School of Integrated Traditional and Western Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
,
Li Chu
1   Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
› Author Affiliations
Further Information

Publication History

received 07 November 2012
revised 12 April 2013

accepted 17 April 2013

Publication Date:
22 May 2013 (online)

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Abstract

The traditional Chinese medicinal herb Danshen (Salvia miltiorrhiza), first recorded in the “Shen Nongʼs Herbal Classic”, has long been used to treat cardiovascular conditions, although the mechanism(s) underlying its effects remain unclear. Here, an iron dextran injection (50 mg · kg−1 per day) was delivered intraperitoneally to establish a mouse model for investigating the ameliorative effects of Danshen injection (low dose at 3 g · kg−1 per day or high dose at 6 g · kg−1 per day) on iron overload-induced cardiac damage. The iron-chelating agent deferoxamine (100 mg · kg−1 per day) was administered as a positive control. The main constituents of Danshen injection, salvianic acid A (danshensu), protocatechuic aldehyde, and salvianolic acid B, were quantified at concentrations of 2.15, 0.44, and 1.01 mg · mL−1, respectively, using HPLC with UV detection. Danshen injection significantly lowered cardiac iron deposition and the concentration of the lipid oxidation product malondialdehyde, as well as improved cardiac superoxide dismutase and glutathione peroxidase levels in iron-overloaded mice. Serum levels of creatine kinase, creatine kinase isoenzyme, and lactate dehydrogenase in the iron-overloaded mice were significantly elevated (up to ~ 160 %), whereas their activities were downregulated by Danshen injection by 25 ~ 35 % at the high dose and by ~ 20 % at the low dose. Morphological changes of cardiac tissue analyzed by hematoxylin and eosin staining indicated that lesions induced by iron overload could be ameliorated by Danshen injection dose-dependently. Altogether, these results illustrated that the protective effects of Danshen injection were at least in part due to decreased iron deposition and inhibition of lipid peroxidation.

Key words

Salvia miltiorrhiza - Lamiaceae - cardioprotection - antioxidation - HPLC-UV

* These authors contributed equally to this work.


 

  • References

  • 1 Andrews NC. Disorders of iron metabolism. N Engl J Med 1999; 341: 1986-1995
    CrossrefPubMedSearch in Google Scholar
  • 2 Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell 2004; 117: 285-297
    CrossrefPubMedSearch in Google Scholar
  • 3 Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 2005; 105: 1867-1874
    CrossrefPubMedSearch in Google Scholar
  • 4 Omara FO, Blakley BR. Influence of low dietary iron and iron overload on urethan-induced lung tumors in mice. Can J Vet Res 1993; 57: 209-211
    PubMedSearch in Google Scholar
  • 5 Herbert V. Iron worsens high-cholesterol-related coronary artery disease. Am J Clin Nutr 1994; 60: 299-300
    PubMedSearch in Google Scholar
  • 6 McCord JM. Effects of positive iron status at a cellular level. Nutr Rev 1996; 54: 85-88
    PubMedSearch in Google Scholar
  • 7 Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (Berl) 2006; 84: 349-364
    CrossrefPubMedSearch in Google Scholar
  • 8 Steensma DP, Hoyer JD, Fairbanks VF. Hereditary red blood cell disorders in middle eastern patients. Mayo Clin Proc 2001; 76: 285-293
    CrossrefPubMedSearch in Google Scholar
  • 9 Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110: 1107-1119
    CrossrefPubMedSearch in Google Scholar
  • 10 Cecchetti G, Binda A, Piperno A, Nador F, Fargion S, Fiorelli G. Cardiac alterations in 36 consecutive patients with idiopathic haemochromatosis: polygraphic and echocardiographic evaluation. Eur Heart J 1991; 12: 224-230
    PubMedSearch in Google Scholar
  • 11 Palka P, Macdonald G, Lange A, Burstow DJ. The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis. J Am Soc Echocardiogr 2002; 15: 884-890
    PubMedSearch in Google Scholar
  • 12 Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997; 89: 739-761
    PubMedSearch in Google Scholar
  • 13 Niederau C, Fischer R, Sonnenberg A. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985; 313: 1256-1262
    CrossrefPubMedSearch in Google Scholar
  • 14 Olivieri NF. The beta-thalassemias. N Engl J Med 1999; 341: 99-109
    CrossrefPubMedSearch in Google Scholar
  • 15 Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet 2000; 355: 2051-2052
    CrossrefPubMedSearch in Google Scholar
  • 16 Galanello R. Iron chelation: new therapies. Semin Hematol 2001; 38: 73-76
    CrossrefPubMedSearch in Google Scholar
  • 17 Chaston TB, Richardson DR. Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity. Am J Hematol 2003; 73: 200-210
    CrossrefPubMedSearch in Google Scholar
  • 18 Wang G, Wang L, Xiong ZY, Mao B, Li TQ. Compound salvia pellet, a traditional Chinese medicine, for the treatment of chronic stable angina pectoris compared with nitrates: a meta-analysis. Med Sci Monit 2006; 12: SR1-SR7
    PubMedSearch in Google Scholar
  • 19 Zhao GR, Zhang HM, Ye TX, Xiang ZJ, Yuan YJ, Guo ZX, Zhao LB. Characterization of the radical scavenging and antioxidant activities of danshensu and salvianolic acid B. Food Chem Toxicol 2008; 46: 73-81
    PubMedSearch in Google Scholar
  • 20 Yokozawa T, Dong E, Oura H, Kashiwagi H, Nonaka G, Nishioka I. Magnesium lithospermate B suppresses the increase of active oxygen in rats after subtotal nephrectomy. Nephron 1997; 75: 88-93
    CrossrefPubMedSearch in Google Scholar
  • 21 Moon CY, Ku CR, Cho YH, Lee EJ. Protocatechuic aldehyde inhibits migration and proliferation of vascular smooth muscle cells and intravascular thrombosis. Biochem Biophys Res Commun 2012; 423: 116-121
    CrossrefPubMedSearch in Google Scholar
  • 22 Gambling L, Charania Z, Hannah L, Antipatis C, Lea RG, Mcardle HJ. Effect of iron deficiency on placental cytokine expression and fetal growth in the pregnant rat. Biol Reprod 2002; 66: 516-523
    CrossrefPubMedSearch in Google Scholar
  • 23 Link G, Konijn AM, Hershko C. Cardioprotective effect of alpha-tocopherol, ascorbate, deferoxamine, and deferiprone: mitochondrial function in cultured, iron-loaded heart cells. J Lab Clin Med 1999; 133: 179-188
    CrossrefPubMedSearch in Google Scholar
  • 24 Livrea MA, Tesoriere L, Pintaudi AM, Calabrese A, Maggio A, Freisleben HJ, DʼArpa D, DʼAnna R, Bongiorno A. Oxidative stress and antioxidant status in beta-thalassemia major: iron overload and depletion of lipid-soluble antioxidants. Blood 1996; 88: 3608-3614
    PubMedSearch in Google Scholar
  • 25 Cheng TO. Cardiovascular effects of Danshen. Int J Cardiol 2007; 121: 9-22
    CrossrefPubMedSearch in Google Scholar
  • 26 Cheng TO. Danshen: a versatile Chinese herbal drug for the treatment of coronary heart disease. Int J Cardiol 2006; 113: 437-438
    CrossrefPubMedSearch in Google Scholar
  • 27 Zhou L, Zuo Z, Chow MS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol 2005; 45: 1345-1359
    CrossrefPubMedSearch in Google Scholar
  • 28 Wang M, Liu J, Zhou B, Xu R, Tao L, Ji M, Zhu L. Acute and sub-chronic toxicity studies of Danshen injection in Sprague-Dawley rats. J Ethnopharmacol 2012; 141: 96-103
    CrossrefPubMedSearch in Google Scholar
  • 29 Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008; 22: 659-661
    CrossrefPubMedSearch in Google Scholar
  • 30 Han JY, Fan JY, Horie Y, Miura S, Cui DH, Ishii H, Hibi T, Tsuneki H, Kimura I. Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. Pharmacol Ther 2008; 117: 280-295
    CrossrefPubMedSearch in Google Scholar
  • 31 Zhou R, He LF, Li YJ, Shen Y, Chao RB, Du JR. Cardioprotective effect of water and ethanol extract of Salvia miltiorrhiza in an experimental model of myocardial infarction. J Ethnopharmacol 2012; 139: 440-446
    CrossrefPubMedSearch in Google Scholar
  • 32 Link G, Tirosh R, Pinson A, Hershko C. Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as a major site of iron-anthracycline interaction. J Lab Clin Med 1996; 127: 272-278
    CrossrefPubMedSearch in Google Scholar
  • 33 Vanella A, Campisi A, di Giacomo C, Sorrenti V, Vanella G, Acqaviva R. Enhanced resistance of adriamycin-treated MCR-5 lung fibroblasts by increased intracellular glutathione peroxidase and extracellular antioxidants. Biochem Mol Med 1997; 62: 36-41
    CrossrefPubMedSearch in Google Scholar
  • 34 Saad SY, Najjar TA, Al-Rikabi AC. The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol Res 2001; 43: 211-218
    CrossrefPubMedSearch in Google Scholar
  • 35 Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, Fleming KA. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med 1998; 339: 417-423
    CrossrefPubMedSearch in Google Scholar
  • 36 Tsushima RG, Wickenden AD, Bouchard RA, Oudit GY, Liu PP, Backx PH. Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: possible implications in iron overload. Circ Res 1999; 84: 1302-1309
    CrossrefPubMedSearch in Google Scholar
  • 37 Benzie IF. Lipid peroxidation: a review of causes, consequences, measurement and dietary influences. Int J Food Sci Nutr 1996; 47: 233-261
    CrossrefPubMedSearch in Google Scholar
  • 38 Dawson EA, Shave R, George K, Whyte G, Ball D, Gaze D, Collinson P. Cardiac drift during prolonged exercise with echocardiographic evidence of reduced diastolic function of the heart. Eur J Appl Physiol 2005; 94: 305-309
    CrossrefPubMedSearch in Google Scholar
  • 39 Chow SN, Wu CC, Huang SC, Tsai YL, Chien CH. Combined analysis of serum lactic dehydrogenase levels and isozyme patterns in ovarian neoplasms. Proc Natl Sci Counc Repub China B 1991; 15: 101-104
    PubMedSearch in Google Scholar
  • 40 de Zwart LL, Meerman JH, Commandeur JN, Vermeulen NP. Biomarkers of free radical damage applications in experimental animals and in humans. Free Radic Biol Med 1999; 26: 202-226
    CrossrefPubMedSearch in Google Scholar
  • 41 Gutteridge JM. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 1995; 41: 1819-1828
    PubMedSearch in Google Scholar
  • 42 Fridovich I. Oxygen radicals from acetaldehyde. Free Radic Biol Med 1989; 7: 557-558
    CrossrefPubMedSearch in Google Scholar
  • 43 Forman HJ, Dickinson DA. Introduction to serial reviews on 4-hydroxy-2-nonenal as a signaling molecule. Free Radic Biol Med 2004; 37: 594-596
    CrossrefPubMedSearch in Google Scholar
  • 44 Huang WM, Yan H, Jin JM, Yu C, Zhang H. Beneficial effects of berberine on hemodynamics during acute ischemic left ventricular failure in dogs. Chin Med J (Engl) 1992; 105: 1014-1019
    PubMedSearch in Google Scholar