نقش پنتوکسی فیلین در بهبود اسپرماتوژنز وکاهش آپاپتوز در آسیب بیضه ناشی از تورشن در مدل حیوانی

نوع مقاله : مقاله پژوهشی

نویسندگان

1 گروه آناتومی، دانشکده پزشکی دانشگاه علوم پزشکی اصفهان، اصفهان، ایران

2 گروه آناتومی، دانشکده علوم پایه پزشکی، دانشگاه اولابیسی اونابانجو ، نیجریه

3 گروه آناتومی، دانشکده پزشکی دانشگاه علوم پزشکی تهران، تهران، ایران

چکیده

مقدمه و هدف: چرخش طناب بیضه‌ای یا تورشن (Torsion) منجر به تشکیل رادیکال‌های آزاد و نهایتاً آپاپتوز می‌شود که در پاتوفیزیولوژی آسیب بیضه نقش مهمی دارد. گزارش‌های اخیر نقش محافظتی پنتوکسی فیلین (PTX) در برابر رادیکال‌های آزاد را مشخص کرده‌اند؛ بنابراین، ما در این مطالعه اثر پنتوکسی فیلین را در آسیب بیضه ناشی از تورشن بررسی کردیم.
مواد و روش ها: 20 موش نر (6 هفته) به 4 گروه 5 تایی تقسیم شدند. گروه کنترل (در شرایط تورشن بدون جراحی)، T1 (تورشن همراه با تک‌دوز mg/kg/Ip100 پنتوکسی‌فیلین)، T2 (تورشن همراه با mg/kg/Ip/d25 پنتوکسی‌فیلین به مدت 2 هفته) و T/D (تورشن- دتورشن). حیوانات در گروه‌هایT1 ، T2 و T/D تحت چرخش 720 درجه طناب اسپرماتیک بیضه سمت چپ در جهت عقربه‌های ساعت به مدت 2 ساعت و به دنبال آن 30 دقیقه عدم چرخش قرار گرفتند. پس از دتورشن، تجویز دارو به‌صورت داخل صفاقی انجام شد. بیضه چپ همه حیوانات در روز 35‌ام پس از تورشن برای سنجش هیستوپاتولوژی و بیوشیمیایی برداشته شدند.
نتایج: تجزیه و تحلیل هیستومورفولوژیکی لوله‌های منی‌ساز بیضه نشان داد که میانگین قطر لوله، نمره جانسون و تعداد سلول‌های زایا در گروه T1 در مقایسه با T2 و T/D افزایش قابل توجهی وجود داشت (P≤0.05)، اما در تعداد سلول‌های سرتولی، لیدیگ و میوئید در همه گروه‌ها اختلاف معنا‌داری مشاهده نشد (P≤ 0.05). تجزیه و تحلیل شاخص‌های استرس اکسیداتیو نشان داد که پنتوکسی‌فیلین سطح SOD، کاتالاز، بیان mRNA ژن‌های  Aktوpi3k را افزایش می‌دهد (P≤0.05) و میزان MDA و سطح کاسپاز 3 در T1 و T2 در مقایسه با T/D را کاهش می‌دهد (P≤0.05). تحلیل آماری توسط نرم‌افزار SPSS با استفاده از تست Tukey انجام شد.
نتیجه‌گیری: پنتوکسی‌فیلین می‌تواند به‌عنوان یک درمان کمکی بعد از جراحی در درمان آسیب بیضه مربوط به تورشن استفاده شود. هرچند، مطالعات بیشتری برای ارزیابی اثرات پنتوکسی‌فیلین در این زمینه لازم است.

کلیدواژه‌ها

موضوعات

عنوان مقاله [English]

The effect of pentoxifylline in improvement of spermatogenesis and apoptosis reduction in testicular damage induced by torsion in an animal model

نویسندگان [English]

  • Mehrnoush Malekzadeh 1
  • Omotosho Dhulqarnain Akanji 2
  • Tayebeh Rastegar 3
1 Department of Anatomy, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Anatomy, Faculty of Basic Medical Sciences, Olabisi Onabanjo University, Sagamu, Ogun State, Nigeria
3 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
چکیده [English]

Background and Objective: Torsion leads to the formation of free radicals and eventually apoptosis, which plays an important role in the pathophysiology of testicular damage. Recent reports have focused on the role of pentoxifylline (PTX) against free radicals. Therefore, in this study, we investigated the effect of pentoxifylline on testicular injury due to torsion.
Materials and Methods: 20 male mice (6 weeks) were divided into 4 groups. Control group (Sham torsion operation), T1 (torsion with single-dose of 100 mg/kg of pentoxifylline, T2 (torsion with 25 mg/kg/d for 2 weeks) and T/D (Torsion-Detorsion). Animals in groups T1, T2 and T/D were subjected to 720° rotation of the left testicular spermatic cord clockwise for 2 hours followed by 30 minutes of detorsion. After detour, the drug was administered intraperitoneally. The left testicles of all animals were removed on day 35 after torsion for histopathological and biochemical evaluation. Statistical analysis was done by SPSS software using Tukey's test.
Results: Micromorphological analysis of testicular seminiferous tubules showed that there was a significant increase in mean tubular diameter, Johnson scores and number of germ cells in T1 group as compared to T2 and T/D (P< 0.05). However, no significant difference was observed in the number of Sertoli, Leydig and Myoid cells in all groups (P<0.05). Analysis of oxidative stress indices showed that pentoxifylline increased the level of SOD, catalase, mRNA expression of Akt and pi3k genes (P < 0.05) and reduced the amount of MDA and caspase-3 levels in T1 and T2 as compared with T/D (P ≤ 0.05).
Conclusion: Pentoxifylline can be used as a supplementary drug after surgery to treat torsion. However, further studies are needed to evaluate the effects of pentoxifylline in this area.

کلیدواژه‌ها [English]

  • Pentoxifylline
  • Torsion
  • Spermatogenesis
  • Apoptosis

مراجع

  1. D Dokmeci - Folia medica. Testicular torsion, oxidative stress and the role of antioxidant therapy. Folia Medica. 2006; 48:16-21
  2. Taneli F, Vatansever S, Ulman C, Yılmaz Ö, Giray G, Genç A, Taneli C . The effect of spermatic vessel ligation on testicular nitric oxide levels and germ cell-specific apoptosis in rat testis. Acta histochemica. 2005;106(6):459-466.
  3. Tusat M, Mentese A, Demir S, Alver A, Imamoglu M. Medical ozone therapy reduces oxidative stress and testicular damage in an experimental model of testicular torsion in rats. International Brazilian Journal of Urology. 2017; 43(6): 1160-1166.
  4. Anim J, Kehinde E, Prasad A, Varghese R. Morphological responses of the rabbit testis to ischemic/reperfusion injury due to torsion. Urologia internationalis. 2005; 75(3):258-63.5.
  5. Chan F, Oatley MJ, Kaucher AV, Yang Q-E, Bieberich CJ, Shashikant CS, et al. Functional and molecular features of the Id4+ germline stem cell population in mouse testes. Genes & development. 2014; 28(12):1351-62.
  6. Orazizadeh M, Hashemitabar M, Khorsandi L. Protective effect of minocycline on dexamethasone induced testicular germ cell apoptosis in mice. European Review for Medical and Pharmacological Sciences. 2009; 13(1): 1-5.
  7. Ringdahl EN, Teague L. Testicular torsion. American family physician. 2006; 74(10): 1739-43.
  8. Ünsal A, Eroglu M, Avci A, Cimentepe E, Guven C, Derya Balbay M, Durak I. Protective role of natural antioxidant supplementation on testicular tissue after testicular torsion and detorsion. Scandinavian journal of Urology and Nephrology. 2006; 40(1): 17-22.
  9. Etensel B, Özkısacık S, Özkara E, Serbest YA, Öztan O, Gürsoy H. The protective effect of dexpanthenol on testicular atrophy at 60th day following experimental testicular torsion. Pediatric surgery international. 2007; 23(3): 271-5.
  10. Kazemi-Darabadi S, Asadpour R, Shahbazfar AA, Alizadeh S, editors. Effects of L-carnitine and betamethasone on ischemia-reperfusion injuries and sperm parameters following testicular torsion in a rat model. Veterinary Research Forum. 2019; 10(2): 125-132.
  11. Chen Yao, Gang Li, Yeyong Qian, Ming Cai, Hong Yin,  Li Xiao,  Wei Tang, Fengjie Guo, and Bingyi Shi . Protection of pentoxifylline against testis injury induced by intermittent hypobaric hypoxia. Oxidative medicine and cellular longevity. 2016; https://doi.org/10.1155/2016/3406802.
  12. Salahshoor MR, Faramarzi A, Roshankhah S, Jalili C. The protective effect of Pentoxifylline on testopathy in male rats following Dimethyl Nitrosamine administration: An experimental study. International Journal of Reproductive BioMedicine. 2019; 17(10): 727-34.
  13. Savas C, Dindar H, Bilgehan A, Ataoglu O, Yucesan S. Pentoxifylline attenuates reperfusion injury in testicular torsion. Scandinavian journal of urology and nephrology. 2002; 36(1):65-70.
  14. Akanji Omotosho Dhulqarnain , Nasrin Takzaree , Golamreza Hassanzadehb,Heidar Tooli , Mehrnoush Malekzadeh, Nasrin Khanmohammadi, Mahsa Yaghobinejad,Somayeh Solhjoo, Tayebeh Rastegar. Pentoxifylline improves the survival of spermatogenic cells via oxidative stress suppression and upregulation of PI3K/AKT pathway in mouse model of testicular torsion-detorsion. Heliyon, 2021; 7(4): 7-14
  15. Jeena K, Liju VB, Kuttan R. Antioxidant, anti-inflammatory and antinociceptive activities of essential oil from ginger. Indian Journal Physiology and Pharmacology. 2013; 57(1):51-62.
  16. Stephen A. McCartney, Larissa B. Thackray, Leonid Gitlin, Susan Gilfillan, Herbert W. Virgin IV, Marco Colonna. MDA-5 Recognition of a Murine Norovirus. PLOS Pathogens. 2008; 4(10): https://doi.org/10.1371/journal.ppat.1000108.
  17. Solhjoo S, Akbari M, Toolee H, Mortezaee K, Mohammadipour M, Nematollahi‐Mahani SN, Shahrokhi, Sayadi M, Rastegar T. Roles for osteocalcin in proliferation and differentiation of spermatogonial cells cocultured with somatic cells. Journal of cellular biochemistry. 2019; 120(4):4924-34.
  18. Toolee H, Rastegar T, Solhjoo S, Mortezaee K, Mohammadipour M, Kashani IR, Akbari M. Roles for Kisspeptin in proliferation and differentiation of spermatogonial cells isolated from mice offspring when the cells are cocultured with somatic cells. Journal of cellular biochemistry. 2019; 120(4): 5042-54.
  19. Karaguzel E, Kadihasanoglu M, Kutlu O. Mechanisms of testicular torsion and potential protective agents. Nature Reviews Urology. 2014; 11(7): 391-9.
  20. Boettcher M, Meier D, Jiménez-Alcázar M, Eschenburg G, Mietzsch S, Vincent D, et al. Degradation of extracellular DNA by DNase1 significantly reduces testicular damage after testicular torsion in rats. Urology. 2017; 109: 1-7.
  21. ayatli F, Akkuş D, Kilic E, Saraymen R, Sönmez MF. The protective effects of grape seed extract on MDA, AOPP, apoptosis and eNOS expression in testicular torsion: an experimental study. World journal of urology. 2013; 31(3): 615-22.
  22. Panagiota Tsounapi, Motoaki Saito, Fotios Dimitriadis, Shogo Shimizu, Yukako Kinoshita, Kohei Shomori, Itaru Satoh, Keisuke Satoh. Protective effect of sivelestat, a neutrophil elastase inhibitor, on ipsilateral and contralateral testes after unilateral testicular ischaemia–reperfusion injury in rats. BJU international. 2011; 107(2):329-336.
  23. Takhtfooladi MA, Moayer F, Takhtfooladi HA. Beneficial effect of pentoxifylline into the testis of rats in an experimental model of unilateral hindlimb ischemia/reperfusion injury. International Brazilian Journal of Urology. 2015; 41(3): 476-83.
  24. Vigueras R, Reyes G, Rojas-Castaneda J, Rojas P, Hernandez R. Testicular torsion and its effects on the spermatogenic cycle in the contralateral testis of the rat. Laboratory animals. 2004; 38(3): 313-20.
  25. Wilhelm Filho D, Torres MA, Bordin AL, Crezcynski-Pasa TB, Boveris A. Spermatic cord torsion, reactive oxygen and nitrogen species and ischemia–reperfusion injury. Molecular aspects of medicine. 2004; 25(1-2): 199-210.
  26. Ozmen S, Ayhan S, Demir Y, Siemionow M, Atabay K. Impact of gradual blood flow increase on ischaemia–reperfusion injury in the rat cremaster microcirculation model. Journal of plastic, reconstructive & aesthetic surgery. 2008; 61(8): 939-48.
  27. Aguilar A, Alvarez-Vijande R, Capdevila S, Alcoberro J, Alcaraz A. Antioxidant Patterns (Superoxide Dismutase, Glutathione Reductase, and Glutathione Peroxidase) in Kidneys From Non–Heart-Beating-Donors: Experimental Study. Transplantation Proceedings. 2007; 39(1): 249-52.
  28. Elahi MM, Kong YX, Matata BM. Oxidative stress as a mediator of cardiovascular disease. Oxidative medicine and cellular longevity. 2009; 2(5): 259-69.
  29. Cetin Pekcetin, Bekir Ugur Ergur, Muge Kiray, Alper Bagriyanik, Kazim Tugyan, Guven Erbil,  Candan Ozogul . The protective effects of trimetazidine on testicular ischemia and reperfusion injury in rats. Pediatric surgery international. 2007; 23(11): 1108-13.
  30. Elshaari F, Elfagih R, Sheriff D, Barassi I. Oxidative and antioxidative defense system in testicular torsion/detorsion. Indian journal of urology: IJU: journal of the Urological Society of India. 2011; 27(4): 470-79.
  31. Keseroglu BB, Ozer E, Karakan T, Ozgur BC, Surer H, Ogus E, et al. Protective effects of Ranolazine on testicular torsion and detorsion injury in rats. Andrologia. 2020; 52(7): e13616.
  32. Semercioz A, Baltaci AK, Mogulkoc R, Avunduk MC. Effect of zinc and melatonin on oxidative stress and serum inhibin-B levels in a rat testicular torsion–detorsion model. Biochemical genetics. 2017; 55(5): 395-409.
  33. Belhan S, Yıldırım S, Karasu A, Kömüroğlu AU, Özdek U. Investigation of the protective role of chrysin within the framework of oxidative and inflammatory markers in experimental testicular ischaemia/reperfusion injury in rats. Andrologia. 2020; 52(9): e 13714.
  34. Turner T, Tung KS, Tomomasa H, Wilson LW. Acute testicular ischemia results in germ cell-specific apoptosis in the rat. Biology of reproduction. 2019; 57(6): 1267-74.
  35. Salahshoor MR, Jalili C, Abdolmaleki A, Roshankhah S. Pentoxifylline modulation hepatotoxicity and apoptosis induced by nitrosamine in rats. Biomedical and Biotechnology Research Journal (BBRJ). 2020; 4(3): 251-9.
  36. Cruz-Galvez CC, Ortiz-Lazareno PC, Pedraza-Brindis EJ, Villasenor-Garcia MM, Reyes-Uribe E, Bravo-Hernandez A, et al. Pentoxifylline enhances the apoptotic effect of carboplatin in Y79 retinoblastoma cells. in vivo. 2019; 33(2): 401-12.
  37. Guowei Zhang, Kaijun Liu, Xi Ling, Zhi Wang, Peng Zou, Xiaogang Wang, Jianfang Gao, Li Yin, Xi Zhang, Jinyi Liu, Lin Ao, Jia Cao. DBP-induced endoplasmic reticulum stress in male germ cells causes autophagy, which has a cytoprotective role against apoptosis in vitro and in vivo. Toxicology letters. 2019; 245:86-98.
  38. Xu G, Zhang W, Bertram P, Zheng XF, McLeod H. Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. International journal of oncology. 2004; 24(4): 893-900.
  39. D'amelio M, Cavallucci V, Cecconi F. Neuronal caspase-3 signaling: not only cell death. Cell Death & Differentiation. 2010; 17(7): 1104-14.
  40. Reza Elmimehr, Ali Motamed-Sanaye, Balal Brazvan, Seyed-Hosein Abtahi-Eivary, Maryam Moghimian, Masoumeh Fani. Effects of hypothermia and pentoxifylline on the adnexal torsion/detorsion injuries in a rat testis model. Andrologia. 2021; 53(8): e14143.
  41. Lee J-D, Jeng S-Y, Lee T-H. Increased activated caspase-3 expression in testicular germ cells of varicocele-induced rats. Journal of Taiwan Urological Association. 2006; 17(3): 81-6.
  42. Young-Ok Son, Lei Wang, Pratheeshkumar Poyil, Amit Budhraja, J. Andrew Hitron, Zhuo Zhang, Jeong-Chae Lee and Xianglin Shi. Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling. Toxicology and applied pharmacology. 2012; 264(2): 153-60.
  43. Mi Hyun Seo , Dae Won Kim , Yeon Sook Kim , Suk Keun Lee. Pentoxifylline-induced protein expression change in RAW 264.7 cells as determined by immunoprecipitation-based high performance liquid chromatography. PLoS One. 2022; 17(3): 1-44
  44. Mohamed M. Elseweidy, Sousou I. Ali,   Mohamed A. Shaheen,  Asmaa M. Abdelghafour  and  Sally K. Hammad.  Vanillin and pentoxifylline ameliorate isoproterenol-induced myocardial injury in rats via the Akt/HIF-1α/VEGF signaling pathway. Food & Function. 2023; 14(7): 3067-3082.
  45. Omotosho Dhulqarnain Akanji , Golamreza Hassanzadeh  , Mehrnoush Malekzadeh  , Nasrin Khanmohammadi  , Maryam Khanezad  , Ghazaleh Sadeghiani  and Tayebeh Rastegar. Pentoxifylline promotes spermatogenesis via upregulation of the Nrf2-ARE signalling pathway in a mouse model of germ-cell apoptosis induced by testicular torsion– Reproduction, Fertility and Development. 2023; 35(7) 423-432.
دانشور پزشکی
دوره 31، شماره 2 - شماره پیاپی 165
خرداد و تیر 1402
صفحه 1-15

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