DOI QR코드

DOI QR Code

Protective effects of curcumin against methotrexate-induced testicular damage in rats by suppression of the p38-MAPK and nuclear factor-kappa B pathways

  • Kilinc, Leyla (Department of Histology and Embryology, Faculty of Medicine, Trakya University) ;
  • Uz, Yesim Hulya (Department of Histology and Embryology, Faculty of Medicine, Trakya University)
  • 투고 : 2021.02.17
  • 심사 : 2021.04.21
  • 발행 : 2021.09.30

초록

Objective: The present study aimed to investigate the possibility that curcumin (CMN) protects against methotrexate (MTX)-induced testicular damage by affecting the phospho-p38 (p-p38) mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. Methods: Eighteen male Wistar albino rats were randomly divided into three groups. The control group was given an intragastric administration of dimethyl sulfoxide (DMSO) daily for 14 days, the MTX group was given a single intraperitoneal dose of MTX (20 mg/kg) on the 11th day, and the MTX+CMN group was given intragastric CMN (100 mg/kg/day, dissolved in DMSO) for 14 days and a single intraperitoneal dose of MTX (20 mg/kg) on the 11th day. At the end of the experiment, all animals were sacrificed and the testicular tissues were removed for morphometry, histology, and immunohistochemistry. Body and testicular weights were measured. Results: Body weights, seminiferous tubule diameter, and germinal epithelium height significantly decreased in the MTX group compared to the control group. Whereas, the number of histologically damaged seminiferous tubules and interstitial space width significantly increased in the MTX group. In addition, the number of p-p38 MAPK immunopositive cells and the immunoreactivity of NF-κB also increased in the MTX group compared to the control group. CMN improved loss of body weight, morphometric values, and histological damage due to MTX. CMN also reduced the number of p-p38 MAPK immunopositive cells and the NF-κB immunoreactivity. Conclusion: CMN may reduce MTX-induced testicular damage by suppressing the p38 MAPK and NF-κB signaling pathways.

키워드

과제정보

This study was supported by Trakya University Scientific Research Projects (TUBAP 2013/126).

참고문헌

  1. Cole PD, Zebala JA, Alcaraz MJ, Smith AK, Tan J, Kamen BA. Pharmacodynamic properties of methotrexate and Aminotrexate during weekly therapy. Cancer Chemother Pharmacol 2006;57:826-34. https://doi.org/10.1007/s00280-005-0115-3
  2. Hashkes PJ, Becker ML, Cabral DA, Laxer RM, Paller AS, Rabinovich CE, et al. Methotrexate: new uses for an old drug. J Pediatr 2014;164:231-6. https://doi.org/10.1016/j.jpeds.2013.10.029
  3. Weber-Schoendorfer C, Hoeltzenbein M, Wacker E, Meister R, Schaefer C. No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study. Rheumatology (Oxford) 2014;53:757-63. https://doi.org/10.1093/rheumatology/ket390
  4. Sener G, Eksioglu-Demiralp E, Cetiner M, Ercan F, Sirvanci S, Gedik N, et al. L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death. Cell Biol Toxicol 2006;22:47-60. https://doi.org/10.1007/s10565-006-0025-0
  5. Semet M, Paci M, Saias-Magnan J, Metzler-Guillemain C, Boissier R, Lejeune H, et al. The impact of drugs on male fertility: a review. Andrology 2017;5:640-63. https://doi.org/10.1111/andr.12366
  6. Aslankoc R, Ozmen O, Ellidag HY. Ameliorating effects of agomelatine on testicular and epididymal damage induced by methotrexate in rats. J Biochem Mol Toxicol 2020;34:e22445. https://doi.org/10.1002/jbt.22445
  7. Daggulli M, Dede O, Utangac MM, Bodakci MN, Hatipoglu NK, Penbegul N, et al. Protective effects of carvacrol against methotrexate-induced testicular toxicity in rats. Int J Clin Exp Med 2014;7:5511-6.
  8. Oktar S, Gokce A, Aydin M, Davarci M, Meydan S, Ozturk OH, et al. Beneficial effect of erdosteine on methotrexate-induced testicular toxicity in mice. Toxicol Ind Health 2010;26:433-8. https://doi.org/10.1177/0748233710369666
  9. Morris LF, Harrod MJ, Menter MA, Silverman AK. Methotrexate and reproduction in men: case report and recommendations. J Am Acad Dermatol 1993;29(5 Pt 2):913-6. https://doi.org/10.1016/0190-9622(93)70270-4
  10. Morrison DK. MAP kinase pathways. Cold Spring Harb Perspect Biol 2012;4:a011254. https://doi.org/10.1101/cshperspect.a011254
  11. Grab J, Rybniker J. The expanding role of p38 mitogen-activated protein kinase in programmed host cell death. Microbiol Insights 2019;12:1178636119864594.
  12. Segreto HR, Oshima CT, Franco MF, Silva MR, Egami MI, Teixeira VP, et al. Phosphorylation and cytoplasmic localization of MAPK p38 during apoptosis signaling in bone marrow granulocytes of mice irradiated in vivo and the role of amifostine in reducing these effects. Acta Histochem 2011;113:300-7. https://doi.org/10.1016/j.acthis.2009.12.002
  13. Shen L, Tang X, Wei Y, Long C, Tan B, Wu S, et al. Vitamin E and vitamin C attenuate Di-(2-ethylhexyl) phthalate-induced blood-testis barrier disruption by p38 MAPK in immature SD rats. Reprod Toxicol 2018;81:17-27. https://doi.org/10.1016/j.reprotox.2018.06.015
  14. Kim YJ, Song M, Ryu JC. Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway. Toxicology 2009;256:183-90. https://doi.org/10.1016/j.tox.2008.11.016
  15. Cho HW, Park SK, Heo KW, Hur DY. Methotrexate induces apoptosis in nasal polyps via caspase cascades and both mitochondria-mediated and p38 mitogen-activated protein kinases/Jun N-terminal kinase pathways. Am J Rhinol Allergy 2013;27:e26-31. https://doi.org/10.2500/ajra.2013.27.3849
  16. Beutheu Youmba S, Belmonte L, Galas L, Boukhettala N, Bole-Feysot C, Dechelotte P, et al. Methotrexate modulates tight junctions through NF-κB, MEK, and JNK pathways. J Pediatr Gastroenterol Nutr 2012;54:463-70. https://doi.org/10.1097/MPG.0b013e318247240d
  17. King TJ, Georgiou KR, Cool JC, Scherer MA, Ang ES, Foster BK, et al. Methotrexate chemotherapy promotes osteoclast formation in the long bone of rats via increased pro-inflammatory cytokines and enhanced NF-κB activation. Am J Pathol 2012;181:121-9. https://doi.org/10.1016/j.ajpath.2012.03.037
  18. Mukherjee S, Ghosh S, Choudhury S, Adhikary A, Manna K, Dey S, et al. Pomegranate reverses methotrexate-induced oxidative stress and apoptosis in hepatocytes by modulating Nrf2-NF-κB pathways. J Nutr Biochem 2013;24:2040-50. https://doi.org/10.1016/j.jnutbio.2013.07.005
  19. van't Land B, Blijlevens NM, Marteijn J, Timal S, Donnelly JP, de Witte TJ, et al. Role of curcumin and the inhibition of NF-kappaB in the onset of chemotherapy-induced mucosal barrier injury. Leukemia 2004;18:276-84. https://doi.org/10.1038/sj.leu.2403233
  20. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002;2:301-10. https://doi.org/10.1038/nrc780
  21. Belhan S, Comakli S, Kucukler S, Gulyuz F, Yildirim S, Yener Z. Effect of chrysin on methotrexate-induced testicular damage in rats. Andrologia 2019;51:e13145. https://doi.org/10.1111/and.13145
  22. Gokce A, Oktar S, Koc A, Yonden Z. Protective effects of thymoquinone against methotrexate-induced testicular injury. Hum Exp Toxicol 2011;30:897-903. https://doi.org/10.1177/0960327110382564
  23. Koc F, Erisgin Z, Tekelioglu Y, Takir S. The effect of beta glucan on MTX induced testicular damage in rats. Biotech Histochem 2018;93:70-5.
  24. Maremanda KP, Jena GB. Methotrexate-induced germ cell toxicity and the important role of zinc and SOD1: Investigation of molecular mechanisms. Biochem Biophys Res Commun 2017;483:596-601. https://doi.org/10.1016/j.bbrc.2016.12.098
  25. Oufi HG, Al-Shawi NN. The effects of different doses of silibinin in combination with methotrexate on testicular tissue of mice. Eur J Pharmacol 2014;730:36-40. https://doi.org/10.1016/j.ejphar.2014.02.010
  26. Pinar N, Cakirca G, Ozgur T, Kaplan M. The protective effects of alpha lipoic acid on methotrexate induced testis injury in rats. Biomed Pharmacother 2018;97:1486-92. https://doi.org/10.1016/j.biopha.2017.11.078
  27. Yulug E, Turedi S, Alver A, Turedi S, Kahraman C. Effects of resveratrol on methotrexate-induced testicular damage in rats. ScientificWorldJournal 2013;2013:489659.
  28. Hemeida RA, Mohafez OM. Curcumin attenuates methotraxate-induced hepatic oxidative damage in rats. J Egypt Natl Canc Inst 2008;20:141-8.
  29. Jantan I, Bukhari SN, Lajis NH, Abas F, Wai LK, Jasamai M. Effects of diarylpentanoid analogues of curcumin on chemiluminescence and chemotactic activities of phagocytes. J Pharm Pharmacol 2012;64:404-12. https://doi.org/10.1111/j.2042-7158.2011.01423.x
  30. Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, et al. Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncol Rep 2018;39:1523-31.
  31. Sun L, Liu Z, Wang L, Cun D, Tong HH, Yan R, et al. Enhanced topical penetration, system exposure and anti-psoriasis activity of two particle-sized, curcumin-loaded PLGA nanoparticles in hydrogel. J Control Release 2017;254:44-54. https://doi.org/10.1016/j.jconrel.2017.03.385
  32. Wang Q, Ye C, Sun S, Li R, Shi X, Wang S, et al. Curcumin attenuates collagen-induced rat arthritis via anti-inflammatory and apoptotic effects. Int Immunopharmacol 2019;72:292-300. https://doi.org/10.1016/j.intimp.2019.04.027
  33. Yang R, Wang J, Zhou Z, Qi S, Ruan S, Lin Z et al. Curcumin promotes burn wound healing in mice by upregulating caveolin-1 in epidermal stem cells. Phytother Res 2019;33:422-30. https://doi.org/10.1002/ptr.6238
  34. Moshari S, Nejati V, Najafi G, Razi M. Nanomicelle curcumin-induced DNA fragmentation in testicular tissue: correlation between mitochondria dependent apoptosis and failed PCNA-related hemostasis. Acta Histochem 2017;119:372-81. https://doi.org/10.1016/j.acthis.2017.03.007
  35. Moreira-Pinto B, Costa L, Fonseca BM, Rebelo I. Dissimilar effects of curcumin on human granulosa cells: beyond its anti-oxidative role. Reprod Toxicol 2020;95:51-8. https://doi.org/10.1016/j.reprotox.2020.04.069
  36. Itokawa H, Shi Q, Akiyama T, Morris-Natschke SL, Lee KH. Recent advances in the investigation of curcuminoids. Chin Med 2008; 3:11. https://doi.org/10.1186/1749-8546-3-11
  37. Nagpal M, Sood S. Role of curcumin in systemic and oral health: an overview. J Nat Sci Biol Med 2013;4:3-7. https://doi.org/10.4103/0976-9668.107253
  38. Choudhary D, Chandra D, Kale RK. Modulation of radioresponse of glyoxalase system by curcumin. J Ethnopharmacol 1999;64:1-7. https://doi.org/10.1016/S0378-8741(98)00064-6
  39. Mahmood K, Zia KM, Zuber M, Salman M, Anjum MN. Recent developments in curcumin and curcumin based polymeric materials for biomedical applications: a review. Int J Biol Macromol 2015;81:877-90. https://doi.org/10.1016/j.ijbiomac.2015.09.026
  40. Ulubay M, Alkan I, Yurt KK, Kaplan S. The protective effect of curcumin on the diabetic rat kidney: a stereological, electron microscopic and immunohistochemical study. Acta Histochem 2020; 122:151486. https://doi.org/10.1016/j.acthis.2019.151486
  41. Aydin MS, Caliskan A, Kocarslan A, Kocarslan S, Yildiz A, Gunay S, et al. Intraperitoneal curcumin decreased lung, renal and heart injury in abdominal aorta ischemia/reperfusion model in rat. Int J Surg 2014;12:601-5. https://doi.org/10.1016/j.ijsu.2014.04.013
  42. Song WB, Wang YY, Meng FS, Zhang QH, Zeng JY, Xiao LP, et al. Curcumin protects intestinal mucosal barrier function of rat enteritis via activation of MKP-1 and attenuation of p38 and NF-κB activation. PLoS One 2010;5:e12969. https://doi.org/10.1371/journal.pone.0012969
  43. Ilbey YO, Ozbek E, Cekmen M, Simsek A, Otunctemur A, Somay A. Protective effect of curcumin in cisplatin-induced oxidative injury in rat testis: mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. HumReprod 2009;24:1717-25.
  44. Vardi N, Parlakpinar H, Ates B, Cetin A, Otlu A. Antiapoptotic and antioxidant effects of beta-carotene against methotrexate-induced testicular injury. Fertil Steril 2009;92:2028-33. https://doi.org/10.1016/j.fertnstert.2008.09.015
  45. Orazizadeh M, Khorsandi L, Absalan F, Hashemitabar M, Daneshi E. Effect of beta-carotene on titanium oxide nanoparticles-induced testicular toxicity in mice. J Assist Reprod Genet 2014;31:561-8. https://doi.org/10.1007/s10815-014-0184-5
  46. Uz YH, Murk W, Bozkurt I, Kizilay G, Arici A, Kayisli UA. Increased c-Jun N-terminal kinase activation in human endometriotic endothelial cells. Histochem Cell Biol 2011;135:83-91. https://doi.org/10.1007/s00418-010-0770-2
  47. Altay B, Cetinkalp S, Doganavsargil B, Hekimgil M, Semerci B. Streptozotocin-induced diabetic effects on spermatogenesis with proliferative cell nuclear antigen immunostaining of adult rat testis. Fertil Steril 2003;80 Suppl 2:828-31. https://doi.org/10.1016/S0015-0282(03)00984-1
  48. Caglar Y, Ozgur H, Matur I, Yenilmez ED, Tuli A, Gonlusen G, et al. Ultrastructural evaluation of the effect of N-acetylcysteine on methotrexate nephrotoxicity in rats. Histol Histopathol 2013;28:865-74.
  49. Chabner BA, Allegra CJ, Curt GA, Clendeninn NJ, Baram J, Koizumi S, et al. Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest 1985;76:907-12. https://doi.org/10.1172/JCI112088
  50. Chabner BA, Amrein PC, Druker BJ, Michaelson MD, Mitsiades CS, Goss PE, et al. Chemotherapy of neoplastic diseases. Chemotherapy of neoplastic diseases. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill; 2006. p. 1335-6.
  51. Babiak RM, Campello AP, Carnieri EG, Oliveira MB. Methotrexate: pentose cycle and oxidative stress. Cell Biochem Funct 1998;16:283-93. https://doi.org/10.1002/(SICI)1099-0844(1998120)16:4<283::AID-CBF801>3.0.CO;2-E
  52. Sukhotnik I, Nativ O, Roitburt A, Bejar D, Coran AG, Mogilner JG, et al. Methotrexate induces germ cell apoptosis and impairs spermatogenesis in a rat. Pediatr Surg Int 2013;29:179-84. https://doi.org/10.1007/s00383-012-3197-0
  53. Padmanabhan S, Tripathi DN, Vikram A, Ramarao P, Jena GB. Methotrexate-induced cytotoxicity and genotoxicity in germ cells of mice: intervention of folic and folinic acid. Mutat Res 2009;673:43-52. https://doi.org/10.1016/j.mrgentox.2008.11.011
  54. Armagan A, Uzar E, Uz E, Yilmaz HR, Kutluhan S, Koyuncuoglu HR, et al. Caffeic acid phenethyl ester modulates methotrexate-induced oxidative stress in testes of rat. Hum Exp Toxicol 2008;27:547-52. https://doi.org/10.1177/0960327108092293
  55. El-Sheikh AA, Morsy MA, Al-Taher AY. Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexate-induced testicular damage. Life Sci 2014;119:40-6. https://doi.org/10.1016/j.lfs.2014.10.015
  56. Nouri HS, Azarmi Y, Movahedin M. Effect of growth hormone on testicular dysfunction induced by methotrexate in rats. Andrologia 2009;41:105-10. https://doi.org/10.1111/j.1439-0272.2008.00897.x
  57. Padmanabhan S, Tripathi DN, Vikram A, Ramarao P, Jena GB. Cytotoxic and genotoxic effects of methotrexate in germ cells of male Swiss mice. Mutat Res 2008;655:59-67. https://doi.org/10.1016/j.mrgentox.2008.07.003
  58. Saxena AK, Dhungel S, Bhattacharya S, Jha CB, Srivastava AK. Effect of chronic low dose of methotrexate on cellular proliferation during spermatogenesis in rats. Arch Androl 2004;50:33-5. https://doi.org/10.1080/01485010490250533
  59. Shrestha S, Dhungel S, Saxena AK, Bhattacharya S, Maskey D. Effect of methotrexate (MTX) administration on spermatogenesis: an experimental on animal model. Nepal Med Coll J 2007;9:230-3.
  60. Wang Y, Zhao TT, Zhao HY, Wang H. Melatonin protects methotrexate-induced testicular injury in rats. Eur Rev Med Pharmacol Sci 2018;22:7517-25.
  61. Yi X, Tang D, Cao S, Li T, Gao H, Ma T, et al. Effect of different exercise loads on testicular oxidative stress and reproductive function in obese male mice. Oxid Med Cell Longev 2020;2020:3071658.
  62. Taha SH, Zaghloul HS, Ali AA, Rashed LA, Sabry RM, Gaballah IF. Molecular and hormonal changes caused by long-term use of high dose pregabalin on testicular tissue: the role of p38 MAPK, oxidative stress and apoptosis. Mol Biol Rep 2020;47:8523-33. https://doi.org/10.1007/s11033-020-05894-6
  63. Li MW, Mruk DD, Cheng CY. Mitogen-activated protein kinases in male reproductive function. Trends Mol Med 2009;15:159-68. https://doi.org/10.1016/j.molmed.2009.02.002
  64. Xiong X, Zhang L, Fan M, Han L, Wu Q, Liu S, et al. β-Endorphin induction by psychological stress promotes Leydig cell apoptosis through p38 MAPK pathway in male rats. Cells 2019;8:1265. https://doi.org/10.3390/cells8101265
  65. Wang T, Zhang X, Li JJ. The role of NF-kappaB in the regulation of cell stress responses. Int Immunopharmacol 2002;2:1509-20. https://doi.org/10.1016/S1567-5769(02)00058-9
  66. Camacho-Barquero L, Villegas I, Sanchez-Calvo JM, Talero E, Sanchez-Fidalgo S, Motilva V, et al. Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmacol 2007;7:333-42. https://doi.org/10.1016/j.intimp.2006.11.006
  67. Chauhan PS, Singh DK, Dash D, Singh R. Intranasal curcumin regulates chronic sthma in mice by modulating NF-κB activation and MAPK signaling. Phytomedicine 2018;51:29-38. https://doi.org/10.1016/j.phymed.2018.06.022
  68. Geng S, Wang S, Zhu W, Xie C, Li X, Wu J, et al. Curcumin suppresses JNK pathway to attenuate BPA-induced insulin resistance in LO2 cells. Biomed Pharmacother 2018;97:1538-43. https://doi.org/10.1016/j.biopha.2017.11.069
  69. Morsy MA, Ibrahim SA, Amin EF, Kamel MY, Rifaai RA, Hassan MK. Curcumin ameliorates methotrexate-induced nephrotoxicity in rats. Adv Pharmacol Sci 2013;2013:387071. https://doi.org/10.1155/2013/387071
  70. Glombik K, Basta-Kaim A, Sikora-Polaczek M, Kubera M, Starowicz G, Styrna J. Curcumin influences semen quality parameters and reverses the di(2-ethylhexyl)phthalate (DEHP)-induced testicular damage in mice. Pharmacol Rep 2014;66:782-7. https://doi.org/10.1016/j.pharep.2014.04.010