Protective effects of Mito-TEMPO on ischemia-reperfusion injury in a mouse testicular torsion and detorsion model

Document Type : Original Article

Authors

1 DVSc Candidate, Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

2 Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

3 Department of Theriogenology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

4 Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

Abstract
Testicular ischemia-reperfusion (I/R) injury during testicular torsion is strongly influenced by oxidative stress caused by excessive accumulation of unscavenged reactive oxygen species. This study aimed to investigate the effects of intra-peritoneal administration of Mito-TEMPO (MT) on I/R injury in testicular torsion/detorsion (T/D) in mice. Forty-two male mice were divided into seven groups including 1 control and 6 treatment groups (360° T/D, 720° T/D, 360° T/D + 0.70 mg kg-1 MT, 360° T/D + 1.00 mg kg-1 MT, 720° T/D + 0.70 mg kg-1 MT, and 720° T/D + 1.00 mg kg-1 MT). After inducing 360° and 720° clockwise testicular torsions for 2 hr, sperm parameters, apoptosis-related genes expression, and in vivo fertility index were evaluated. The results showed that 720° T/D can lead to increased abnormal sperm morphology, sperm DNA damage, and Bax expression, while the Bcl-2 expression was reduced compared to the other groups. In addition, it also had negative effects on sperm total and progressive motilities as well as viability and plasma membrane functionality (PMF). The results also showed that administration of MT to T/D mice can result in a reduction in abnormal sperm morphology, DNA damage, and Bax expression. It could also increase sperm total and progressive motilities, viability and PMF, Bcl-2 expression, and in vivo fertility index. Based on our results, it is concluded that MT, when administered after spermatic cord torsion in mice, provides significant protection against acute testicular T/D injury.

Keywords

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  1. Karaguzel E, Kadihasanoglu M, Kutlu O. Mechanisms of testicular torsion and potential protective agents. Nat Rev Urol 2014; 11(7): 391-399.
  2. Sessions AE, Rabinowitz R, Hulbert WC, et al. Testicular torsion: direction, degree, duration and disinformation. J Urol 2003; 169(2): 663-665.
  3. Raisi A, Davoodi F. Testicular torsions in veterinary medicine. Vet Res Commun 2022; 46(2): 303-313.
  4. Raisi A, Davoodi F, Mohammadi R. Protective effects of rosmarinic acid on testicular torsion-detorsion in an animal model. Iran J Vet Surg 2022; 17(2): 80-86.
  5. Volpe CMO, Villar-Delfino PH, Dos Anjos PMF, et al. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis 2018; 9(2): 119. doi: 10.1038/s41419-017-0135-z.
  6. Arroyo S, de la Morena A. Life-threatening adverse events of antiepileptic drugs. Epilepsy Res 2001; 47(1-2): 155-174.
  7. Ayan M, Tas U, Sogut E, et al. Protective effect of thymoquinone against testicular torsion induced oxidative injury. Andrologia 2016; 48(2): 143-151.
  8. Conti M, Morand PC, Levillain P, et al. Improved fluorometric determination of malonaldehyde. Clin Chem 1991; 37(7): 1273-1275.
  9. Mogilner JG, Elenberg Y, Lurie M, et al. Effect of dexamethasone on germ cell apoptosis in the contralateral testis after testicular ischemia-reperfusion injury in the rat. Fertil Steril 2006; 85(Suppl 1): 1111-1117.
  10. Smith RA, Murphy MP. Mitochondria-targeted antioxidants as therapies. Discov Med 2011; 11(57): 106-114.
  11. Masoudi R, Asadzadeh N, Sharafi M. Effects of freezing extender supplementation with mitochondria-targeted antioxidant Mito-TEMPO on frozen-thawed rooster semen quality and reproductive performance. Anim Reprod Sci 2021; 225: 106671 doi: 10.1016/ j.anireprosci.2020.106671.
  12. Choumar A, Tarhuni A, Lettéron P, et al. Lipopoly saccharide-induced mitochondrial DNA depletion. Antioxid Redox Signal 2011; 15(11): 2837-2854.
  13. Ni R, Cao T, Xiong S, et al. Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy. Free Radic Biol Med 2016; 90: 12-23.
  14. Jamshidi HR, Emami A, Golmohammadi H, et al. Protective Effect of Mito-TEMPO on sodium valproate-induced hepatotoxicity in mice. Acta Med Iran 2020; 58(7): 352-357.
  15. Davoodi F, Taheri S, Raisi A, et al. Investigating the sperm parameters, oxidative stress and histopathological effects of salvia miltiorrhiza hydroalcoholic extract in the prevention of testicular ischemia reperfusion damage in rats. Theriogenology 2020; 144: 98-106.
  16. Soleimanzadeh A, Pourebrahim M, Delirezh N, et al. Ginger ameliorates reproductive toxicity of formaldehyde in male mice: evidences for Bcl-2 and Bax. J Herbmed Pharmacol 2018; 7(4): 259-266.
  17. Cao W, Aghajanian HK, Haig-Ladewig LA, et al. Sorbitol can fuel mouse sperm motility and protein tyrosine phosphorylation via sorbitol dehydrogenase. Biol Reprod 2009; 80(1): 124-133.
  18. Ramazani N, Mahd Gharebagh F, Soleimanzadeh A, et al. The influence of L‐proline and fulvic acid on oxidative stress and semen quality of buffalo bull semen following cryopreservation. Vet Med Sci 2023; 9(4): 1791-1802.
  19. WHO laboratory manual for the examination and processing of human semen. 6th ed. Geneva, Switzerland: Department of reproductive health and research; 2021.
  20. Taheri S, Davoodi F, Raisi A, et al. Co‐administration of Salvia miltiorrhiza and verapamil inhibits detrimental effects of torsion/detorsion on testicular tissue in rats. Andrologia 2021; 53(6): e14049. doi: 10.1111/ and.14049.
  21. Sarlak M, Roumiani E, Kheradmand A, et al. Evaluating the effects of betaine on testicular ischemia/ reperfusion injury induced by torsion/detorsion in the rat. Andrologia 2022; 54(10): e14559. doi: 10.1111/ and.14559.
  22. Webb A, Bond R, McLean P, et al. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci U S A. 2004; 101(37): 13683-13688.
  23. Kazaz IO, Mentese A, Demir S, et al. Berberine inhibits the ischemia-reperfusion induced testicular injury through decreasing oxidative stress. Am J Emerg Med 2020; 38(1): 33-37.
  24. Mogilner JG, Lurie M, Coran AG, et al. Effect of diclofenac on germ cell apoptosis following testicular ischemia-reperfusion injury in a rat. Pediatr Surg Int 2006; 22(1): 99-105.
  25. Aitken RJ, Roman SD. Antioxidant systems and oxidative stress in the testes. Oxid Med Cell Longev 2008; 1(1): 15-24.
  26. Güney C, Coşkun KA, Tutar Y. ATPase inhibition by omeprazole reveals role of heat shock proteins on testicular torsion. Andrologia 2020; 53(2): e13929. doi: 10.1111/and.13929.
  27. Puja IK, Sawitri NM, Maharani N, et al. Preservation of semen from Kintamani Bali dogs by freezing method. J Adv Vet Anim Res 2019; 6(2): 158-162.
  28. Ramazani N, Mahd Gharebagh F, Soleimanzadeh A, et al. Reducing oxidative stress by κ-carrageenan and C60HyFn: the post-thaw quality and antioxidant status of Azari water buffalo bull semen. Cryobiology 2023; 111: 104-112.
  29. Ruiz‐Pesini E, Díez‐Sánchez C, López‐Pérez MJ, et al. The role of the mitochondrion in sperm function: is there a place for oxidative phosphorylation or is this a purely glycolytic process? Curr Top Dev Biol 2007; 77: 3-19.
  30. Fang L, Bai C, Chen Y, et al. Inhibition of ROS production through mitochondria-targeted antioxidant and mitochondrial uncoupling increases post-thaw sperm viability in yellow catfish. Cryobiology 2014; 69(3): 386-393.
  31. Sertkaya Z, Öztürk Mİ, Koca O, et al. Prohylactic effects of verapamil in testicular ischemia-reperfusion damage in rats. Haydarpasa Numune Med J 2020; 60(3): 279-283.
  32. Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. BJU Int 2005; 95(4): 503-507.
  33. Camhi SL, Lee P, Choi AM. The oxidative stress response. New Horiz 1995; 3(2): 170-182.
  34. Soleimanzadeh A, Saberivand A, Ahmadi A. Effect of α-tocopherol on spermatozoa of rat semen after the freeze-thawing process [Persian]. Urmia Med J 2014; 25(9): 826-834.
  35. Filho DW, Torres MA, Bordin AL, et al. Spermatic cord torsion, reactive oxygen and nitrogen species and ischemia-reperfusion injury. Mol Aspects Med 2004; 25(1-2): 199-210.
  36. Masoudi R, Asadzadeh N, Sharafi M. The mitochondria-targeted antioxidant Mito-TEMPO conserves rooster’s cooled semen quality and fertility potential. Theriogenology 2020; 156: 236-241.
  37. Zarei F, Daghigh-Kia H, Masoudi R. Supplementation of ram’s semen extender with Mito-TEMPO II: quality evaluation and flow cytometry study of post-thawed spermatozoa. Andrologia 2022; 54(1): e14299. doi: 10.1111/and.14299.
  38. Dhulqarnain AO, Takzaree N, Hassanzadeh G, et al. 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): e06868. doi: 10.1016/j.heliyon.2021.e06868.
  39. Lysiak JJ, Nguyen QA, Kirby JL, et al. Ischemia-reperfusion of the murine testis stimulates the expression of proinflammatory cytokines and activation of c-jun N-terminal kinase in a pathway to E-selectin expression. Biol Reprod 2003; 69(1): 202-210.
  40. D’amelio M, Cavallucci V, Cecconi F. Neuronal caspase-3 signaling: not only cell death. Cell Death Differ 2010; 17(7): 1104-1114.
  41. Turner TT, Tung KS, Tomomasa H, et al. Acute testicular ischemia results in germ cell-specific apoptosis in the rat. Biol Reprod 1997; 57(6): 1267-1274.
  42. Ozen OA, Kus MA, Kus I, et al. Protective effects of melatonin against formaldehyde-induced oxidative damage and apoptosis in rat testes: an immunohistochemical and biochemical study. Syst Biol Reprod Med 2008; 54(4-5): 169-176.
  43. Trnka J, Blaikie FH, Logan A, et al. Antioxidant properties of MitoTEMPOL and its hydroxylamine. Free Radic Res 2009; 43(1): 4-12.
  44. Hu H, Li M. Mitochondria-targeted antioxidant mitotempo protects mitochondrial function against amyloid beta toxicity in primary cultured mouse neurons. Biochem Biophys Res Commun 2016; 478(1): 174-180.
  45. Hadziselimovic F, Geneto R, Emmons LR. Increased apoptosis in the contralateral testes of patients with testicular torsion as a factor for infertility. J Urol 1998; 160(3 Pt 2): 1158-1160.
  46. Shokoohi M, Olad Saheb Madarek E, Khaki A, et al. Investigating the effects of onion juice on male fertility factors and pregnancy rate after testicular torsion/ detorsion by intrauterine insemination method. Int J Womens Health Reprod Sci 2018; 6(4): 499-505.
  47. Qamar AY, Naveed MI, Raza S, et al. Role of antioxidants in fertility preservation of sperm - a narrative review. Anim Biosci 2023; 36(3): 385-403.
  48. Mehmood A, Anwar M, Naqvi SMS. Motility, acrosome integrity, membrane integrity and oocyte cleavage rate of sperm separated by swim-up or Percoll gradient method from frozen-thawed buffalo semen. Anim Reprod Sci 2009; 111(2-4): 141-148.
  49. Lu X, Zhang Y, Bai H, et al. Mitochondria-targeted antioxidant MitoTEMPO improves the post-thaw sperm quality. Cryobiology 2018; 80: 26-29.
  50. Zhang X, Lu X, Li J, et al. Mito-Tempo alleviates cryodamage by regulating intracellular oxidative metabolism in spermatozoa from asthenozoospermic patients. Cryobiology 2019; 91: 18-22.
Volume 15, Issue 12
December 2024
Pages 665-672

  • Receive Date 13 March 2024
  • Revise Date 09 April 2024
  • Accept Date 07 May 2024