Protection against cisplatin-induced nephrotoxicity by Spirulina in rats

  • Iyyapu Krishna Mohan
  • Mahmood Khan
  • Jagdish Chandra Shobha
  • Madireddy Umamaheswara Rao Naidu
  • Aruna Prayag
  • Periannan Kuppusamy
  • Vijay Kumar Kutala
Original Article

Abstract

Purpose: Cisplatin (CP)-induced nephrotoxicity is associated with the increased generation of reactive oxygen metabolites and lipid peroxidation in kidney, caused by the decreased levels of antioxidants and antioxidant enzymes. The purpose of this study was to evaluate the role of Spirulina, blue–green alga with antioxidant properties, in the protection of cisplatin-induced nephrotoxicity in rat. Methods: Rats were treated with CP (6 mg/kg bw, single dose, intraperitoneally). Spirulina (1,000 mg/kg) was administered orally for 8 days and CP treatment was given on day 4. Nephrotoxicity was assessed, 6 days after the CP treatment, by measuring plasma urea, creatinine, urinary N-acetyl-(d-glucose-aminidase) (β-NAG) and histopathology of kidney. Results: Rats treated with CP showed marked nephrotoxicity as evidenced from the significant elevation in plasma urea, creatinine and urinary β-NAG. Histological assessment revealed marked proximal tubular necrosis and extensive epithelial vacuolization in the kidney of CP-treated rats. Superoxide dismutase, catalase and glutathione peroxidase were decreased and lipid peroxidation was increased in kidney tissue. Pretreatment with Spirulina protected the rats from CP-induced nephrotoxicity. The rise in plasma urea, creatinine, urinary β-NAG, plasma and kidney tissue MDA and histomorphological changes were significantly attenuated by Spirulina. In vitro studies using human ovarian cancer cells revealed that Spirulina did not interfere with the cytotoxic effects of CP on tumor cells. Conclusions: In summary, Spirulina significantly protected the CP-induced nephrotoxicity through its antioxidant properties.

Keywords

Cisplatin Nephrotoxicity Spirulina C-phycocyanin Antioxidant 

References

  1. 1.
    Loehrer PJ, Einhorn LH (1984) Drugs five years later Cisplatin. Ann Intern Med 100:704–713PubMedGoogle Scholar
  2. 2.
    Heidemann HT, Muller S, Mertins L, Stepan G, Hoffmann K, Ohnhaus EE (1989) Effect of aminophylline on cisplatin nephrotoxicity in the rat. Br J Pharmacol 97:313–318PubMedGoogle Scholar
  3. 3.
    Safirstein R, Winston J, Moel D, Dikman S, Guttenplan J (1987) Cisplatin nephrotoxicity: insights into mechanism. Int J Androl 10:325–346PubMedCrossRefGoogle Scholar
  4. 4.
    Schaaf GJ, Maas RF, de Groene EM, Fink-Gremmels J (2002) Management of oxidative stress by heme oxygenase-1 in cisplatin-induced toxicity in renal tubular cells. Free Radic Res 36:835–843PubMedCrossRefGoogle Scholar
  5. 5.
    Xiao T, Choudhary S, Zhang W, Ansari NH, Salahudeen A (2003) Possible involvement of oxidative stress in cisplatin-induced apoptosis in LLC-PK1 cells. J Toxicol Environ Health A 66:469–479PubMedCrossRefGoogle Scholar
  6. 6.
    Cummings BS, Schnellmann RG (2002) Cisplatin-induced renal cell apoptosis: caspase 3-dependent and -independent pathways. J Pharmacol Exp Ther 302:8–17PubMedCrossRefGoogle Scholar
  7. 7.
    Baliga R, Zhang Z, Baliga M, Ueda N, Shah SV (1998) In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int 53:394–401PubMedCrossRefGoogle Scholar
  8. 8.
    Rybak LP, Ravi R, Somani SM (1995) Mechanism of protection by diethyldithiocarbamate against cisplatin ototoxicity: antioxidant system. Fundam Appl Toxicol 26:293–300PubMedCrossRefGoogle Scholar
  9. 9.
    Antunes LM, Araujo MC, Darin JD, Bianchi ML (2000) Effects of the antioxidants curcumin and vitamin C on cisplatin-induced clastogenesis in Wistar rat bone marrow cells. Mutat Res 465:131–137PubMedGoogle Scholar
  10. 10.
    Davis CA, Nick HS, Agarwal A (2001) Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide. J Am Soc Nephrol 12:2683–2690PubMedGoogle Scholar
  11. 11.
    Appenroth D, Frob S, Kersten L, Splinter FK, Winnefeld K (1997) Protective effects of vitamin E and C on cisplatin nephrotoxicity in developing rats. Arch Toxicol 71:677–683PubMedCrossRefGoogle Scholar
  12. 12.
    Antunes LM, Francescato HD, Darin JD, de Lourdes PBM (2000) Effects of selenium pretreatment on cisplatin-induced chromosome aberrations in wistar rats. Teratog Carcinog Mutagen 20:341–348PubMedCrossRefGoogle Scholar
  13. 13.
    Sueishi K, Mishima K, Makino K, Itoh Y, Tsuruya K, Hirakata H, Oishi R (2002) Protection by a radical scavenger edaravone against cisplatin-induced nephrotoxicity in rats. Eur J Pharmacol 451:203–208PubMedCrossRefGoogle Scholar
  14. 14.
    Orditura M, De Vita F, Roscigno A, Infusino S, Auriemma A, Iodice P, Ciaramella F, Abbate G, Catalano G (1999) Amifostine: a selective cytoprotective agent of normal tissues from chemo-radiotherapy induced toxicity (Review). Oncol Rep 6:1357–1362PubMedGoogle Scholar
  15. 15.
    Ozen S, Akyol O, Iraz M, Sogut S, Ozugurlu F, Ozyurt H, Odaci E, Yildirim Z (2004) Role of caffeic acid phenethyl ester, an active component of propolis, against cisplatin-induced nephrotoxicity in rats. J Appl Toxicol 24:27–35PubMedCrossRefGoogle Scholar
  16. 16.
    Khan Z, Bhadouria P, Bisen PS (2005) Nutritional and therapeutic potential of Spirulina. Curr Pharm Biotechnol 6:373–379PubMedCrossRefGoogle Scholar
  17. 17.
    Ciferri O (1983) Spirulina, the edible microorganism. Microbiol Rev 47:551–578PubMedGoogle Scholar
  18. 18.
    Miranda MS, Cintra RG, Barros SB, Mancini Filho J (1998) Antioxidant activity of the microalga Spirulina maxima. Braz J Med Biol Res 31:1075–1079PubMedCrossRefGoogle Scholar
  19. 19.
    Remirez D, Gonzalez R, Merino N, Rodriguez S, Ancheta O (2002) Inhibitory effects of Spirulina in zymosan-induced arthritis in mice. Mediators Inflamm 11:75–79PubMedCrossRefGoogle Scholar
  20. 20.
    Chamorro G, Salazar M, Favila L, Bourges H (1996) Pharmacology and toxicology of Spirulina alga. Rev Invest Clin 48:389–399PubMedGoogle Scholar
  21. 21.
    Ayehunie S, Belay A, Baba TW, Ruprecht RM (1998) Inhibition of HIV-1 replication by an aqueous extract of Spirulina platensis (Arthrospira platensis). J Acquir Immune Defic Syndr Hum Retrovirol 18:7–12PubMedGoogle Scholar
  22. 22.
    Khan M, Shobha JC, Mohan IK, Naidu MU, Sundaram C, Singh S, Kuppusamy P, Kutala VK (2005) Protective effect of Spirulina against doxorubicin-induced cardiotoxicity. Phytother Res 19:1030–1037PubMedCrossRefGoogle Scholar
  23. 23.
    Schwartz J, Shklar G, Reid S, Trickler D (1988) Prevention of experimental oral cancer by extracts of Spirulina–Dunaliella algae. Nutr Cancer 11:127–134PubMedCrossRefGoogle Scholar
  24. 24.
    Weijl NI, Hopman GD, Wipkink-Bakker A, Lentjes EG, Berger HM, Cleton FJ, Osanto S (1998) Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol 9:1331–1337PubMedCrossRefGoogle Scholar
  25. 25.
    Horak E, Hopfer SM, Sunderman FW Jr (1981) Spectrophotometric assay for urinary N-acetyl-beta-d-glucosaminidase activity. Clin Chem 27:1180–1185PubMedGoogle Scholar
  26. 26.
    Bernheim FM, Bernheim BL, Wilbur KM (1948) The reaction between TBA and the oxidation products of certain lipids. J Biol Chem 174:257–264PubMedGoogle Scholar
  27. 27.
    McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055PubMedGoogle Scholar
  28. 28.
    Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126PubMedCrossRefGoogle Scholar
  29. 29.
    Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169PubMedGoogle Scholar
  30. 30.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  31. 31.
    Baliga R, Ueda N, Walker PD, Shah SV (1999) Oxidant mechanisms in toxic acute renal failure. Drug Metab Rev 31:971–997PubMedCrossRefGoogle Scholar
  32. 32.
    Somani SM, Ravi R, Rybak LP (1995) Diethyldithiocarbamate protection against cisplatin nephrotoxicity: antioxidant system. Drug Chem Toxicol 18:151–170PubMedCrossRefGoogle Scholar
  33. 33.
    Yilmaz HR, Uz E, Yucel N, Altuntas I, Ozcelik N (2004) Protective effect of caffeic acid phenethyl ester (CAPE) on lipid peroxidation and antioxidant enzymes in diabetic rat liver. J Biochem Mol Toxicol 18:234–238PubMedCrossRefGoogle Scholar
  34. 34.
    Nakano S, Gemba M (1989) Potentiation of cisplatin-induced lipid peroxidation in kidney cortical slices by glutathione depletion. Jpn J Pharmacol 50:87–92PubMedCrossRefGoogle Scholar
  35. 35.
    Kruidering M, Van de Water B, de Heer E, Mulder GJ, Nagelkerke JF (1997) Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. J Pharmacol Exp Ther 280:638–649PubMedGoogle Scholar
  36. 36.
    Richter C, Gogvadze V, Laffranchi R, Schlapbach R, Schweizer M, Suter M, Walter P, Yaffee M (1995) Oxidants in mitochondria: from physiology to Diseases. Biochim Biophys Acta 1271:67–74PubMedGoogle Scholar
  37. 37.
    Sener G, Satiroglu H, Kabasakal L, Arbak S, Oner S, Ercan F, Keyer-Uysa M (2000) The protective effect of melatonin on cisplatin nephrotoxicity. Fundam Clin Pharmacol 14:553–560PubMedGoogle Scholar
  38. 38.
    Shiraishi F, Curtis LM, Truong L, Poss K, Visner GA, Madsen K, Nick HS, Agarwal A (2000) Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis. Am J Physiol Renal Physiol 278:F726–F736PubMedGoogle Scholar
  39. 39.
    Agarwal A, Nick HS (2000) Renal response to tissue injury: lessons from heme oxygenase-1 GeneAblation and expression. J Am Soc Nephrol 11:965–973PubMedGoogle Scholar
  40. 40.
    Bhat VB, Madyastha KM (2000) C-phycocyanin: a potent peroxyl radical scavenger in vivo and in vitro. Biochem Biophys Res Commun 275:20–25PubMedCrossRefGoogle Scholar
  41. 41.
    Romay C, Armesto J, Remirez D, Gonzalez R, Ledon N, Garcia I (1998) Antioxidant and anti-inflammatory properties of C-phycocyanin from blue–green Algae. Inflamm Res 47:36–41PubMedCrossRefGoogle Scholar
  42. 42.
    Khan M, Varadharaj S, Ganesan LP, Shobha JC, Naidu MU, Parinandi NL, Tridandapani S, Kutala VK, Kuppusamy P (2006) C-phycocyanin protects against ischemia–reperfusion injury of heart through involvement of p38 MAPK and ERK signaling. Am J Physiol Heart Circ Physiol (in press)Google Scholar
  43. 43.
    Mathew B, Sankaranarayanan R, Nair PP, Varghese C, Somanathan T, Amma BP, Amma NS, Nair MK (1995) Evaluation of chemoprevention of oral cancer with Spirulina fusiformis. Nutr Cancer 24:197–202PubMedGoogle Scholar
  44. 44.
    Premkumar K, Pachiappan A, Abraham SK, Santhiya ST, Gopinath PM, Ramesh A (2001) Effect of Spirulina fusiformis on cyclophosphamide and mitomycin-C induced genotoxicity and oxidative stress in mice. Fitoterapia 72:906–911PubMedCrossRefGoogle Scholar
  45. 45.
    Upasani CD, Khera A, Balaraman R (2001) Effect of lead with vitamin E, C, or Spirulina on malondialdehyde, conjugated dienes and hydroperoxides in rats. Indian J Exp Biol 39:70–74PubMedGoogle Scholar
  46. 46.
    Premkumar K, Abraham SK, Santhiya ST, Ramesh A (2004) Protective effect of Spirulina fusiformis on chemical-induced genotoxicity in mice. Fitoterapia 75:24–31PubMedCrossRefGoogle Scholar
  47. 47.
    Wang Y, Chang CF, Chou J, Chen HL, Deng X, Harvey BK, Cadet JL, Bickford PC (2005) Dietary supplementation of with blueberries, spinach, or spirulina reduces ischemic brain damage. Exp Neurol 193:75–84PubMedCrossRefGoogle Scholar
  48. 48.
    Farooq SM, Asokan D, Sakthivel R, Kalaiselvi P, Varalakshmi P (2004) Salubrious effect of C-phycocyanin against oxalate-mediated renal cell injury. Clin Chim Acta 348:199–205PubMedCrossRefGoogle Scholar
  49. 49.
    Lau AH (1999) Apoptosis induced by cisplatin nephrotoxic injury. Kidney Int 56:1295–1298PubMedCrossRefGoogle Scholar
  50. 50.
    Wu YJ, Muldoon LL, Neuwelt EA (2005) The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther 312:424–431PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Iyyapu Krishna Mohan
    • 1
  • Mahmood Khan
    • 2
  • Jagdish Chandra Shobha
    • 1
  • Madireddy Umamaheswara Rao Naidu
    • 1
  • Aruna Prayag
    • 3
  • Periannan Kuppusamy
    • 2
  • Vijay Kumar Kutala
    • 1
    • 2
  1. 1.Department of Clinical Pharmacology and TherapeuticsNizam’s Institute of Medical SciencesHyderabadIndia
  2. 2.Davis Heart and Lung Research Institute, Comprehensive Cancer CenterThe Ohio State UniversityColumbusUSA
  3. 3.Department of PathologyNizam’s Institute of Medical SciencesHyderabadIndia

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