Volume 16, Issue 5 (May 2018)                   IJRM 2018, 16(5): 323-334 | Back to browse issues page

XML Persian Abstract Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Hamzeh M, Hosseinimehr S J, Mohammadi H R, Yaghubi Beklar S, Dashti A, Talebpour Amiri F. Atorvastatin attenuates the ovarian damage induced by cyclophosphamide in rat: An experimental study. IJRM 2018; 16 (5) :323-334
URL: http://ijrm.ir/article-1-1108-en.html
Atorvastatin attenuates the ovarian damage induced by cyclophosphamide in rat: An experimental study
Maedeh Hamzeh1 , Seyed Jalal Hosseinimehr2 , Hamid Reza Mohammadi3 , Saeed Yaghubi Beklar4 , Ayat Dashti4 , Fereshteh Talebpour Amiri * 5
1- Department of Anatomy, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran
2- Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
3- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
4- Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
5- Department of Anatomy, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran , ftaleb2001@yahoo.co.uk
Abstract:   (4763 Views)
Background: Cyclophosphamide (CP), as an anticancer agent, causes ovarian toxicity and subsequent infertility in women. Atorvastatin (ATV) at a low dose has antioxidant and anti-inflammatory properties.
Objective: The aim of this study was to investigate the protective effect of ATV against CP-induced ovarian injury in rat.
Materials and Methods: In this experimental study, thirty-two female Wistar rats were randomly divided into four groups as I) control, II) ATV (10 mg/kg), III) CP (150 mg/kg), and IV) CP +ATV. The ATV treated groups were received ATV for 10 days via oral gavage. In the CP+ATV group, ATV was administrated on 5 days before and 5 days after CP injection. Histological structure, apoptosis (caspase-3), oxidative stress parameters as malondialdehyde, reactive oxygen species, protein carbonyl levels and cell viability were evaluated in ovary tissue by histological scores, immunohistochemistry, histochemical and biochemical assays. The levels of estrogen and progesterone hormones were measured on the 12th day of study.
Results: ATV pretreatment significantly decreased the levels of oxidative stress biomarkers as malondialdehyde, reactive oxygen species and protein carbonyl levels and increased cell death in CP-treated rats as compared with the CP alone group. ATV significantly increased estrogen and progesterone levels in CP-treated rats. In addition, the histological examination showed ATV mitigated acute inflammation, degenerative cells in stroma and follicles, stromal edema, vacuolization, atresia of the follicles and congestion of blood vessels in the CP-treated animals. Furthermore, ATV significantly reduced immunoreactivity level of caspase-3 in CP-treated rats.
Conclusion: Our results showed that the ATV with antioxidant and anti-apoptosis (caspase-3) activities protected ovarian against CP-induced toxicity.
Keywords: Cyclophosphamide, Atorvastatin, Ovary, Oxidative stress, Antioxidant
Full-Text [PDF 922 kb]   (1072 Downloads) |   |   Full-Text (HTML)  (2940 Views)  
Type of Study: Original Article |
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29. [DOI:10.3322/caac.21254]
2. Anderson RA, Themmen AP, Al-Qahtani A, Groome NP, Cameron DA. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod 2006; 21: 2583-2592. [DOI:10.1093/humrep/del201]
3. Fleer R, Brendel M. Toxicity, interstrand cross-links and DNA fragmentation induced by 'activated'cyclophosphamide in yeast: comparative studies on 4-hydroperoxy-cyclophosphamide, its monofunctional analogon, acrolein, phosphoramide mustard, and nor-nitrogen mustard. Chem Biol Interact 1982; 39: 1-15. [DOI:10.1016/0009-2797(82)90002-3]
4. Tsai-Turton M, Luong BT, Tan Y, Luderer U. Cyclophosphamide-induced apoptosis in COV434 human granulosa cells involves oxidative stress and glutathione depletion. Toxicol Sci 2007; 98: 216-230. [DOI:10.1093/toxsci/kfm087]
5. Yener NA, Sinanoglu O, Ilter E, Celik A, Sezgin G, Midi A, et al. Effects of spirulina on cyclophosphamide-induced ovarian toxicity in rats: biochemical and histomorphometric evaluation of the ovary. Biochem Res Int 2013; 2013: 764262. [DOI:10.1155/2013/764262]
6. Saleh DO, Mansour DF. Ovario-protective effects of genistein against cyclophosphamide toxicity in rats: Role of anti-müllerian hormone and oestradiol. Eur J Pharmacol 2016; 789: 163-171. [DOI:10.1016/j.ejphar.2016.07.026]
7. Yuksel A, Bildik G, Senbabaoglu F, Akin N, Arvas M, Unal F, et al. The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells. Hum Reprod 2015; 30: 2926-2935. [DOI:10.1093/humrep/dev256]
8. Lambertini M, Anserini P, Levaggi A, Poggio F, Del Mastro L. Fertility counseling of young breast cancer patients. J Thorac Dis 2013; 5 (Suppl.): S68-80.
9. Zhou Q, Liao JK. Pleiotropic effects of statins: basic research and clinical perspectives. Cir J 2010; 74: 818-826. [DOI:10.1253/circj.CJ-10-0110]
10. Fassett RG, Coombes JS. Statins in acute kidney injury: friend or foe? BMJ 2013; 346: f1531. [DOI:10.1136/bmj.f1531]
11. Crevar-Sakac M, Vujić Z, Kotur-Stevuljević J, Ivanisević J, Jelić-Ivanović Z, Milenković M, et al. Effects of atorvastatin and artichoke leaf tincture on oxidative stress in hypercholesterolemic rats. Vojnosanit Pregl 2016; 73: 178-187. [DOI:10.2298/VSP140917148C]
12. Nasri H, Hasanpour Z, Nematbakhsh M, Ahmadi A, Rafieian-Kopaei M. The effect of the various doses of atorvastatin on renal tubular cells; an experimental study. J Nephropathol 2016; 5: 111-115. [DOI:10.15171/jnp.2016.20]
13. Klinefelter GR, Laskey JW, Amann RP. Statin drugs markedly inhibit testosterone production by rat Leydig cells in vitro: Implications for men. Reprod Toxicol 2014; 45: 52-58. [DOI:10.1016/j.reprotox.2013.12.010]
14. Dostal LA, Whitfield LR, Anderson JA. Fertility and general reproduction studies in rats with the HMG-CoA reductase inhibitor, atorvastatin. Fundam Appl Toxicol 1996; 32: 285-292. [DOI:10.1006/faat.1996.0132]
15. Talebpour Amiri F, Hamzeh M, Naeim RA, Ghasemi A, Hosseinimehr SJ. Radioprotective effect of atorvastatin against ionizing radiation-induced nephrotoxicity in mice. Int J Radiat Biol 2018; 94: 106-113. [DOI:10.1080/09553002.2018.1420926]
16. Hamzeh M, Talebpour Amiri F, Karimpour Malekshah A, Yaghubi Beklar S, Hosseinimehr J. [Protective Effect of Atorvastatin against Cardiotoxicity and Hematotoxicity Induced by Cyclophosphamide in Rat.] J Mazandaran Univ Med Sci 2017; 27: 1-11. (in Persian)
17. Naeimi RA, Talebpour Amiri F, Khalatbary AR, Ghasemi A, Zargari M, Ghesemi M, et al. Atorvastatin mitigates testicular injuries induced by ionizing radiation in mice. Reprod Toxicol 2017; 72: 115-121. [DOI:10.1016/j.reprotox.2017.06.052]
18. Parlakgumus HA, Aka Bolat F, Bulgan Kilicdag E, Simsek E, Parlakgumus A. Atorvastatin for ovarian torsion: effects on follicle counts, AMH, and VEGF expression. Eur J Obstet Gynecol Reprod Biol 2014; 175: 186-190. [DOI:10.1016/j.ejogrb.2014.01.017]
19. Fathi H, Ebrahimzadeh MA, Ziar A, Mohammadi H. Oxidative damage induced by retching; antiemetic and neuroprotective role of Sambucus ebulus L. Cell Biol Toxicol 2015; 31: 231-239. [DOI:10.1007/s10565-015-9307-8]
20. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254. [DOI:10.1016/0003-2697(76)90527-3]
21. Zhang F, Xu Z, Gao J, Xu B, Deng Y. In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain. Environ Toxicol Pharmacol 2008; 26: 232-236. [DOI:10.1016/j.etap.2008.04.003]
22. Ghazi-Khansari M, Mohammadi-Bardbori A, Hosseini MJ. Using janus green B to study paraquat toxicity in rat liver mitochondria: role of ACE inhibitors (thiol and nonthiol ACEi). Ann N Y Acad Sci 2006; 1090: 98-107. [DOI:10.1196/annals.1378.010]
23. Eser A, Hizli D, Haltas H, Namuslu M, Kosus A, Kosus N, et al. Effects of curcumin on ovarian ischemia-reperfusion injury in a rat model. Biomed Rep 2015; 3: 807-813. [DOI:10.3892/br.2015.515]
24. Green DM, Kawashima T, Stovall M, Leisenring W, Sklar CA, Mertens AC, et al. Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 2009; 27: 2677-2685. [DOI:10.1200/JCO.2008.20.1541]
25. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 2001; 7: 535-543. [DOI:10.1093/humupd/7.6.535]
26. Devine PJ, Perreault SD, Luderer U. Roles of Reactive Oxygen Species and Antioxidants in Ovarian Toxicity. Biol Reprod 2012; 86: 1-10. [DOI:10.1095/biolreprod.111.095224]
27. Cadirci E, Oral A, Odabasoglu F, Kilic C, Coskun K, Halici Z, et al. Atorvastatin reduces tissue damage in rat ovaries subjected to torsion and detorsion: biochemical and histopathologic evaluation. Naunyn Schmiedeberg's Arch Pharmacol 2010; 381: 455-466. [DOI:10.1007/s00210-010-0504-y]
28. Wassmann S, Laufs U, Müller K, Konkol C, Ahlbory K, Bäumer AT, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2002; 22: 300-305. [DOI:10.1161/hq0202.104081]
29. Ozacmak VH, Sayan H, Igdem AA, Cetin A, Ozacmak ID. Attenuation of contractile dysfunction by atorvastatin after intestinal ischemia reperfusion injury in rats. Eur J Pharmacol 2007; 562: 138-147. [DOI:10.1016/j.ejphar.2007.01.061]
30. Elewa HF, Kozak A, El-Remessy AB, Frye RF, Johnson MH, Ergul A, et al. Early atorvastatin reduces hemorrhage after acute cerebral ischemia in diabetic rats. J Pharmacol Exp Ther 2009; 330: 532-540. [DOI:10.1124/jpet.108.146951]
31. El-Moselhy MA, El-Sheikh AA. Protective mechanisms of atorvastatin against doxorubicin-induced hepato-renal toxicity. Biomed Pharmacother 2014; 68: 101-110. [DOI:10.1016/j.biopha.2013.09.001]
32. Sathyapalan T, Kilpatrick ES, Coady A-M, Atkin SL. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study. J Clin Endocrinol Metab 2009; 94: 103-108. [DOI:10.1210/jc.2008-1750]
33. Jabbour HN, Sales KJ, Catalano RD, Norman JE. Inflammatory pathways in female reproductive health and disease. Reproduction 2009; 138: 903-919. [DOI:10.1530/REP-09-0247]
34. Herath S, Williams EJ, Lilly ST, Gilbert RO, Dobson H, Bryant CE, et al. Ovarian follicular cells have innate immune capabilities that modulate their endocrine function. Reproduction 2007; 134: 683-693. [DOI:10.1530/REP-07-0229]
35. Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N. Reactive oxygen species are indispensable in ovulation. Proc Nati Acad Sci U.S.A. 2011; 108: 1462-1467. [DOI:10.1073/pnas.1017213108]
36. Fujii J, Iuchi Y, Okada F. Fundamental roles of reactive oxygen species and protective mechanisms in the female reproductive system. Reprod Biol Endocrinol 2005; 3: 43. [DOI:10.1186/1477-7827-3-43]
37. Motta A, Estevez A, Tognetti T, Gimeno MA, Franchi AM. Dual effects of nitric oxide in functional and regressing rat corpus luteum. Mol Hum Reprod 2001; 7: 43-47. [DOI:10.1093/molehr/7.1.43]
38. Lopez SG, Luderer U. Effects of cyclophosphamide and buthionine sulfoximine on ovarian glutathione and apoptosis. Free Radic Biol Med 2004; 36: 1366-1377. [DOI:10.1016/j.freeradbiomed.2004.02.067]
39. Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update 2005; 11: 162-178. [DOI:10.1093/humupd/dmi001]
40. Davis BJ, Heindel JJ. Ovarian Toxicants: Multiple Mechanisms. Reprod Dev Toxicol 1998: 373.
41. Desmeules P, Devine PJ. Characterizing the ovotoxicity of cyclophosphamide metabolites on cultured mouse ovaries. Toxicol Sci 2006; 90: 500-509. [DOI:10.1093/toxsci/kfj086]
42. Bao XM, Wu CF, Lu GP. Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK. Atherosclerosis 2010; 210: 114-121. [DOI:10.1016/j.atherosclerosis.2009.11.032]
Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Designed & Developed by : Yektaweb