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The Activities of Antioxidant Enzymes and the Level of Malondialdehyde in Cerebellum of Rats Subjected to Methotrexate: Protective Effect of Caffeic Acid Phenethyl Ester

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Abstract

Methotrexate (MTX), a folic acid antagonist, is widely used as a cytotoxic chemotherapeutic agent. MTX-associated neurotoxicity is an important clinical problem. The aim of this study was to investigate the role of caffeic acid phenethyl ester (CAPE) on cerebellar oxidative stress induced by MTX in rats. A total of 19 adult male rats were divided into three experimental groups as follows: MTX group (MTX treated), MTX+CAPE group (MTX+CAPE treated), and control group. MTX was administered intraperitoneally (i.p.) with a single dose of 20 mg kg−1 on the second day of experiment. CAPE was administered i.p. with a dose of 10 μmol kg−1 day−1 for 7 days. Malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD) and catalase (CAT) were determined in cerebellar tissue of rats. MTX caused to significant increase in MDA levels (an important marker of lipid peroxidation) in the MTX group compared with the controls (p = 0.006). CAPE significantly reduced the MTX induced lipid peroxidation in the MTX+CAPE group compared to the MTX (p = 0.007). The activities of SOD and CAT were significantly increased in the MTX group when compared with the control group (p = 0.0001, p = 0.004, respectively). The increased activities of these enzymes were significantly reduced by CAPE treatment (p = 0.004, p = 0.034, respectively). As a result, CAPE may protect from oxidative damage caused by MTX treatment in rat cerebellum.

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References

  1. Mahoney DH Jr, Shuster JJ, Nitschke R, Lauer SJ, Steuber CP, Winick N, Camitta B: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: An association with intermediate-dose intravenous methotrexate and intrathecal triple therapy: A Pediatric Oncology Group study. J Clin Oncol 16: 1712–1722, 1998

    PubMed  CAS  Google Scholar 

  2. Linnebank M, Pels H, Kleczar N, Farmand S, Fliessbach K, Urbach H, Orlopp K, Klockgether T, Schmidt-Wolf IG, Schlegel U: MTX-induced white matter changes are associated with polymorphisms of methionine metabolism. Neurology 64: 912–913, 2005

    PubMed  CAS  Google Scholar 

  3. Brock S, Jenning HR: Fatal encephalomyelitis after a single dose of intrathecal methotrexate. Pharmacotherapy 24: 673–676, 2004

    Article  PubMed  Google Scholar 

  4. Uzar E, Sahin O, Koyuncuoglu HR, Uz E, Bas O, Kilbas S, Yilmaz HR, Yurekli VA, Kucuker H, Songur A: The activity of adenosine deaminase and the level of nitric oxide in spinal cord of methotrexate administered rats: Protective effect of caffeic acid phenethyl ester. Toxicology 218(2/3): 125–133, 2006

    Article  PubMed  CAS  Google Scholar 

  5. Lesnik PG, Ciesielski KT, Hart BL, Benzel EC, Sanders JA: Evidence for cerebellar-frontal subsystem changes in children treated with intrathecal chemotherapy for leukemia: Enhanced data analysis using an effect size model. Arch Neurol 55: 1561–1568, 1998

    Article  PubMed  CAS  Google Scholar 

  6. El-Badawi MG, Fatani JA, Bahakim H, Abdalla MA: Light and electron microscopic observations on the cerebellum of guinea pigs following low-dose methotrexate. Exp Mol Pathol 53: 211–222, 1990

    Article  PubMed  CAS  Google Scholar 

  7. Gilbert MR, Harding BL, Grossman SA: Methotrexate neurotoxicity: In vitro studies using cerebellar explants from rats. Cancer Res 49: 2502–2505, 1989

    PubMed  CAS  Google Scholar 

  8. Vezmar S, Becker A, Bode U, Jaehde U: Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy 49: 92–104, 2003

    Article  PubMed  CAS  Google Scholar 

  9. Kishi S, Griener J, Cheng C, Das S, Cook EH, Pei D, Hudson M, Rubnitz J, Sandlund JT, Pui CH, Relling MV: Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol 21: 3084–3091, 2003

    Article  PubMed  CAS  Google Scholar 

  10. Quinn CT, Griener JC, Bottiglieri T, Arning E, Winick NJ: Effects of intraventricular methotrexate on folate, adenosine and homocysteine metabolism in cerebrospinal fluid. J Pediatr Hematol Oncol 26: 386–388, 2004

    Article  PubMed  Google Scholar 

  11. Kishi T, Tanaka Y, Ueda K: Evidence for hypomethylation in two children with acute lymphoblastic leukemia and leukoencephalopathy. Cancer 89: 925–931, 2000

    Article  PubMed  CAS  Google Scholar 

  12. Caro AA, Cederbaum AI: Antioxidant properties of S-adenosyl-sc l-methionine in Fe (2+)-initiated oxidations. Free Radic Biol Med 36, 1303–1316, 2004

    Article  PubMed  CAS  Google Scholar 

  13. Villalobos MA, De La Cruz JP, Cuerda MA, Ortiz P, Smith-Agreda JM, Sanchez De La Cuesta F: Effect of S-adenosyl methionine on rat brain oxidative stress damage in a combined model of permanent focal ischemia and global ischemia-reperfusion. Brain Res 883: 31–40, 2000

    Article  PubMed  CAS  Google Scholar 

  14. Frouin I, Prosperi E, Denegri M, Negri C, Donzelli M, Rossi L, Riva F, Stefanini M, Scovassi AI: Different effects of methotrexate on DNA mismatch repair proficient and deficient cells. Eur J Cancer 37(9): 1173–1180, 2001

    Article  PubMed  CAS  Google Scholar 

  15. Neuman MG, Cameron RG, Haber JA, Katz GG, Malkewcz IM, Shear NH: Inducers of cytochrome P450 2E1 enhance methotrexate-induced hepatotoxicity. Clin Biochem 32: 519–536, 1999

    Article  PubMed  CAS  Google Scholar 

  16. Miketova P, Kaemingk K, Hockenberry M, Pasvogel A, Hutter J, Krull K, Moore IM: Oxidative changes in cerebral spinal fluid phosphatidylcholine during treatment for acute lymphoblastic leukemia. Biol Res Nurs 6: 187–195, 2005

    Article  PubMed  Google Scholar 

  17. Husain K, Morris C, Whitworth C, Trammell GL, Rybak LP, Somani SM: Protection by ebselen against cisplatin-induced nephrotoxicity: Antioxidant system. Mol Cell Biochem 178: 127–133, 1998

    Article  PubMed  CAS  Google Scholar 

  18. Uz E, Oktem F, Yilmaz HR, Uzar E, Ozguner F: The activities of purine-catabolizing enzymes and the level of nitric oxid e in rat kidneys subjected to methotrexate: Protective effect of caffeic acid phenethyl ester. Mol Cell Biochem 277(1/2): 165–170, 2005

    Article  PubMed  CAS  Google Scholar 

  19. Oktem F, Ozguner F, Sulak O, Olgar, S. Akturk O, Yilmaz HR, Altuntas I: Lithium-induced renal toxicity in rats: Protection by a novel antioxidant caffeic acid phenethyl ester. Mol Cell Biochem 277: 109–115, 2005

    Article  PubMed  CAS  Google Scholar 

  20. Musavi S, Kakkar P: Effect of diazepam treatment and its withdrawal on pro/antioxidative processes in rat brain. Mol Cell Biochem 245: 51–56, 2003

    Article  PubMed  CAS  Google Scholar 

  21. Cicek E, Sutcu R, Gokalp O, Yilmaz HR, Ozer MK, Uz E, Ozcelik N, Delibas N: The effects of isoniazid on hippocampal NMDA receptors: Protective role of erdosteine. Mol Cell Biochem 277: 131–135, 2005

    Article  PubMed  CAS  Google Scholar 

  22. Cetiner M, Sener G, Sehirli AO, Eksioglu-Demiralp E, Ercan F, Sirvanci S, Gedik N, Akpolat S, Tecimer T, Yegen BC: Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death. Toxicol Appl Pharmacol 209(1): 39–50, 2005

    Article  PubMed  CAS  Google Scholar 

  23. Miyazono Y, Gao F, Horie T: Oxidative stress contributes to methotrexate-induced small intestinal toxicity in rats. Scand J Gastroenterol 39: 1119–1127, 2004

    Article  PubMed  CAS  Google Scholar 

  24. Jahovic N, Cevik H, Sehirli AO, Yegen BC, Sener G: Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res 34: 282–287, 2003

    Article  PubMed  CAS  Google Scholar 

  25. Babiak RM, Campello AP, Carnieri EG, Oliveira MB: Methotrexate: Pentose cycle and oxidative stress. Cell Biochem Funct 16: 283–293, 1998

    Article  PubMed  CAS  Google Scholar 

  26. Ilhan A, Koltuksuz U, Ozen S, Uz E, Ciralik H, Akyol O: The effects of caffeic acid phenethyl ester (CAPE) on spinal cord ischemia reperfusion injury in rabbits. Eur J Cardiothorac Surg 16: 458–463, 1999

    Article  PubMed  CAS  Google Scholar 

  27. Ilhan A, Iraz M, Gurel A, Armutcu F, Akyol O: Caffeic acid phenethyl ester exerts a neuroprotective effect on CNS against pentylenetetrazol-induced seizures in mice. Neurochem Res 29: 2287–2292, 2004

    Article  PubMed  CAS  Google Scholar 

  28. Ozguner F, Oktem F, Armagan A, Yilmaz R, Koyu A, Demirel R, Vural H, Uz E: Comparative analysis of the protective effects of melatonin and caffeic acid phenethyl ester (CAPE) on mobile phone-induced renal impairment in rat. Mol Cell Biochem 276: 31–37, 2005

    Article  PubMed  CAS  Google Scholar 

  29. Ozguner F, Bardak Y, Comlekci S: Protective effects of melatonin and caffeic acid phenethyl ester against retinal oxidative stress in long-term use of mobile phone: A comparative study. Mol Cell Biochem 282: 83–88, 2006

    Article  PubMed  CAS  Google Scholar 

  30. Park EH, Kahng JH: Suppressive effects of propolis in rat adjuvant arthritis. Arch Pharm Res 22: 554–558, 1999

    Article  PubMed  CAS  Google Scholar 

  31. Michaluart P, Masferrer JL, Carothers AM, Subbaramaiah K, Zweifel BS, Koboldt C, Mestre JR, Grunberger D, Sacks PG, Tanabe T, Dannenberg AJ: Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res 59: 2347–2352, 1999

    PubMed  CAS  Google Scholar 

  32. Chen YJ, Shiao MS, Wang SY: The antioxidant caffeic acid phenethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HL-60 cells. Anticancer Drugs 12: 143–149, 2001

    Article  PubMed  CAS  Google Scholar 

  33. Fesen MR, Pommier Y, Leteurtre E, Hiroguchi S, Yung J, Kohn KW: Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds. Biochem Pharmacol 48: 595–608, 1994

    Article  PubMed  CAS  Google Scholar 

  34. Noelker C, Bacher M, Gocke P, Wei X, Klockgether T, Du Y, Dodel R: The flavanoide caffeic acid phenethyl ester blocks 6-hydroxydopamine-induced neurotoxicity. Neurosci Lett 383: 239–243, 2005

    Article  CAS  Google Scholar 

  35. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the folin phenol reagent. J Clin Chem 193: 265–75, 1951

    CAS  Google Scholar 

  36. Draper HH, Hadley M: Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186: 421–431, 1990

    PubMed  CAS  Google Scholar 

  37. Sun Y, Oberley LW, Li Y: A simple method for clinical assay of superoxide dismutase. Clin Chem 34: 497–500, 1988

    PubMed  CAS  Google Scholar 

  38. Aebi H: Catalase in vitro. Methods Enzymol 105: 121–126, 1984

    Article  PubMed  CAS  Google Scholar 

  39. Krokower GR, Kamen BA: In situ methotrexate polyglutamate formation in rat tissues. J Pharmacol Exp Ther 227: 633–638, 1983

    PubMed  Google Scholar 

  40. Irmak MK, Fadillioglu E, Sogut S, Erdogan H, Gulec M, Ozer M, Yagmurca M, Gozukara ME: Effects of caffeic acid phenethyl ester and alpha-tocopherol on reperfusion injury in rat brain. Cell Biochem Funct 21: 283–289, 2003

    Article  PubMed  CAS  Google Scholar 

  41. Yilmaz HR, Uz E, Yucel N, Altuntas I, Ozcelik N: Protective effect of caffeic acid phenethyl ester on lipid peroxidation and antioxidant enzymes in diabetic rat liver. J Biochem Mol Toxicol 18: 234–238, 2004

    Article  PubMed  CAS  Google Scholar 

  42. Yagmurca M, Erdogan H, Iraz M, Songur A, Ucar M, Fadillioglu E: Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats. Clin Chim Acta 348: 27–34, 2004

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Ertugrul Uzar.

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Uzar, E., Koyuncuoglu, H.R., Uz, E. et al. The Activities of Antioxidant Enzymes and the Level of Malondialdehyde in Cerebellum of Rats Subjected to Methotrexate: Protective Effect of Caffeic Acid Phenethyl Ester. Mol Cell Biochem 291, 63–68 (2006). https://doi.org/10.1007/s11010-006-9196-5

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