Protective effect of pentoxifylline on male Wistar rat testicular germ cell apoptosis induced by 3,4-methylenedioxymeth amphetamine

Document Type: Original Article

Authors

1 Department of Medical Sciences, Shahrood Branch, Islamic Azad University, Shahrood, Iran

2 Department of Anatomy, School of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran

3 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Research Center, Tehran University of Medical Sciences, Tehran, Iran

4 Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

5 Department of Anatomy, Iran University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): 3, 4-methylenedioxymethamphetamine (MDMA) one of the methamphetamine derivatives that affect the reproductive system, has not been well understood. Many young people are consumers of drugs such as MDMA that can affect their reproductive capability. Apoptosis is the main mechanism for male infertility. Pentoxifylline (PTX) increases cAMP intracellularly and reduces tumor necrosis factor-α.
This study aimed to investigate the protective effect of PTX administration in MDMA-induced apoptosis in testes of male Wistar rats.
Materials and Methods: Thirty male Wistar rats weighing 250–300 g were randomly divided into five groups: control group (without any intervention), group receiving 7.5 mg/kg MDMA three times every two hours for one day, first experimental group receiving 100 mg/kg PTX just at the time of third injection of MDMA, second experimental group receiving 100 mg/kg PTX a week before MDMA administration, and the vehicle group, which received MDMA+saline.  Two weeks later, testes were removed and prepared for H&E staining, TUNEL and Western blot techniques. 
Results: There was a significant decrease of the score in the MDMA group compared with the control group. In first and second experimental groups, the quality of seminiferous epithelium was improved compared with the MDMA group. The number of TUNEL-positive cells/tubule increased in MDMA and vehicle groups, which is decreased by administration of PTX before MDMA. Expression of active caspase-3 significantly increased in MDMA group, which is significantly decreased by administration of PTX before MDMA.
Conclusion: PTX can significantly reduce the severity of lesions in the testes following administration of MDMA.

Keywords


1. Mirjalili T, Kalantar SM, Shams Lahijani M, Sheikhha MH, Talebi A. Congenital abnormality effect of methamphetamine on histological, cellular and chromosomal defects in fetal mice. Iran J Reprod Med 2013; 11:39-46.

2. Bahora M, Sterk CE, Elifson KW. Understanding recreational ecstasy use in the United States: A qualitative inquiry.  J Drug Policy 2009; 20:62-69.

3. Gore AC, Terasawa E. Neural circuits regulating pulsatile luteinizing hormone release in the female guinea-pig: Opioid, adrenergic and serotonergic interactions. J Neuroendocrinol 2001; 13:239–248.

4. Dickerson SM, Walker DM, Reveron ME, Duvauchelle CL, Gore AC. The recreational drug ecstasy disrupts the hypothalamic-pituitary-gonadal reproductive axis in adult male rats. Neuroendocrinology 2008; 88:95-102.

5. Karami M, Saeidnia S, Nosrati A. Study of the hepatoprotective activity of methanolic extract of Feijoa sellowiana fruits against MDMA using the isolated rat liver perfusion system. Iran J Pharm Res 2013; 12:85-91.

6. Quick MW. Regulating the conducting states of a mammalian serotonin transporter. Neuron 2003; 40: 537-549.

7. Orazizadeh M, Hashemitabar M, Khorsandi L. Protective effect of minocycline on dexamethasone induced testicular germ cell apoptosis in mice. Eur Rev Med Pharmacol Sci 2009; 13:1-5.

8. Hosseini-Zare MS, Salehi F, Seyedi SY, Azami K, Ghadiri T, Mobasseri M, et al. Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice. Eur J Pharmacol 2011; 670:464-70.

9. Maxwell DT, Jacobson JD, King A, Chan PJ. Effect of pentoxifylline on tumor suppressor and proto-oncogene apoptosis in sperm. J Assist Reprod Genet 2002; 19:279-283.

10. Sunil VR, Vayas KN, Cervelli JA, Malaviya R, Hall L, Massa CB, et al. Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation. Exp Mol Pathol 2014; 97: 89-98.

11. Esteves SC, Spaine DM, Cedenho AP. Effects of pentoxifylline treatment before freezing on motility, viability and acrosome status of poor quality human spermatozoa cryopreserved by the liquid nitrogen vapor method. Braz J Med Biol Res 2007; 40:985-992.

12. Zakaria A, Al-Busadah KA. Pentoxifyl line efficiency in protecting testes against cadmium toxicity. J Anim Vet Adv 2015; 14:18-29.

13. Safarinejad MR. Effect of pentoxifylline on semen parameters, reproductive hormones, and seminal plasma antioxidant capacity in men with idiopathic infertility: A randomized double-blind placebo-controlled study.  Int Urol Nephrol 2011; 43:315-328.

14. Wang X, Baumann MH, Xu H, Rothman RB. 3, 4-Methylenedioxymethamphetamine (MDMA) adminis-tration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein. Synapse 2004; 53:240– 248.

15. Barenys M, Macia N, Camps L, de Lapuente J, Gomez-Catalan J, Gonzalez-Linares J, et al. Chronic exposure to MDMA (ecstasy) increases DNA damage in sperm and alters testes histopathology in male rats. Toxicol Lett 2009; 191:40-46.

16. Barenys M, Gomez-Catalan J, Camps L, Teixido E, de Lapuente J, Gonzalez-Linares J, et al. MDMA (ecstasy) delays pubertal development and alters sperm quality after developmental exposure in the rat. Toxicol Lett 2010; 197:135-142.

17. Moguilevsky JA, Wuttke W. Changes in the control of gonadotrophin secretion by neurotransmitters during sexual development in rats. Exp Clin Endocrinol Diabetes 2001; 109:188–195.

18. Wada K, Hu L, Mores N, Navarro CE, Fuda H, Krsmanovic LZ, et al. Serotonin (5-HT) receptor subtypes mediate specific modes of 5-HT-induced signaling and regulation of neurosecretion in gonadotropin-releasing hormone neurons. Mol Endocrinol 2006; 20:125–135.

19. Stumm G, Schlegel J, Schäfer T, Würz C, Mennel HD, Krieg JC, et al. Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons. FASEB J 1999; 13:1065-1072.

20. Aragoَn MA, Ayala ME, Marin M, Avilés A, Damian-Matsumura P, Dominguez R. Serotoninergic system blockage in the prepubertal rat inhibits spermatogenesis development. Reproduction 2005; 129:717–727.

21. Celikel R, Peterson EC, Owens SM, Varughese KI. Crystal structures of a therapeutic single chain antibody in complex with two drugs of abuse-methamphetamine and 3,4 methylenedioxymetham-phetamine. Protein Sci 2009; 18:2336-2345.

22. Esse K, Fossati-Bellani M, Traylor A, Martin-Schild S. Epidemic of illicit drug use, mechanisms of action/addiction and stroke as a health hazard. Brain Behav 2011; 1:44-54.

23. Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: Mechanisms, mutation, and disease. FASEB J 2003; 17:1195-1214.

24. Jones DP. Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 2008; 295:C849-868.

25. Miyamoto Y, Koh YH, Park YS, Fujiwara N, Sakiyama H, Misonou Y,et al. Oxidative stress caused by inactivation of glutathione peroxidase and adaptive responses. Biol Chem 2003; 384: 567-574.

26. Ménézo Y, Dale B, Cohen M. DNA damage and repair in human oocytes and embryos: a review. Zygote 2010; 18:357-365.

27. Hsieh YY, Chang CC, Lin CS. Seminal malondialdehyde concentration but not glutathione peroxidase activity is negatively correlated with seminal concentration and motility. Int J Biol 2006; 2:23-29.

28. Minamiyama Y, Ichikawa H, Takemura S, Kusunoki H, Naito Y, Yoshikawa T. eneration of reactive oxygen species in sperms of rats as an earlier marker for evaluating the toxicity of endocrine-disrupting chemicals. Free Radic Res  2010; 44:1398-1406.

29. Tian C, Murrin LC, Zheng JC. Mitochondrial fragmentation is involved in methamphetamine-induced cell death in rat hippocampal neural progenitor cells. PLoS One 2009; 4:e5546.

30. Aliabadi E, Soleimani-Mehranjani M, Borzoei Z, Talaei-Khozani T, Mirkhani H, Tabesh H. Effects of L-carnitine and L-acetyl-carnitine on testicular sperm motility and chromatin quality. Iran J Reprod Med 2012; 77-82.

31. Horiuchi H, Saito N, Kinoshita T, Wakabayashi S, Tsutsumimoto T, Takaoka K. Enhancement of bone morphogenetic protein-2-induced new bone formation in mice by the phosphodiesterase inhibitor pentoxifylline. Bone 2001; 28:290-294.

32. Beshay E, Croze F, Prud'homme GJ.The phosphodiesterase inhibitors pentoxifylline and rolipram suppress macrophage activation and nitric oxide production in vitro and in vivo. Clin Immunol 2001; 98:272-279.

33. Marcinkiewicz J, Grabowska A, Lauterbach R, Bobek M. Differential effects of pentoxifylline, a non-specific phosphodiesterase inhibitor, on the production of IL-10, IL-12 p40 and p35 subunits by murine peritoneal macrophages. Immunopharmaco-logy 2000; 49:335-343.

34. Movassaghi S, Nadia Sharifi Z, Soleimani M, Joghataii MT, Hashemi M, Shafaroodi H, et al. Effect of pentoxifylline on ischemia- induced brain damage and spatial memory impairment in rat. Iran J Basic Med Sci 2012; 15:1083-1090.

35. Oliva A, Dotta A, Multigner L. Pentoxifylline and antioxidants improve sperm quality in male patients with varicocele. Fertil Steril 2009; 91:1536–1539.

36. Laokirkkiat P, Kunathikom S, Choavaratana R, Petyim S, Prechapanich J.Comparison between sperm treated with pentoxifylline and 2-deoxyadenosine using hypo-osmotic swelling test. J Med Assoc Thai 2007; 90:211–215.

37. Terriou P, Hans E, Giorgetti C , Spach J L, Salzmann J, Urrutia V, et al. Pentoxifylline initiates motility in spontaneously immotile epididymal and testicular spermatozoa and allows normal fertili-zation, pregnancy, and birth after intracytoplasmic sperm injection. J Assist Reprod Genet 2000; 17:194–199.

38. Kovacic B, Vlaisavljevic V, Reljic M. Clinical use of pentoxifylline for activation of immotile testicular sperm before ICSI in patients with azoospermia. J Androl 2006; 27:45-52.

39. Amer M, Metawae B, Hosny H, Raef A. Beneficial effect of adding pentoxifylline to processed semen samples on ICSI outcome in infertile males with mild and moderate asthenozoospermia: A randomized controlled prospective crossover study. Iran J Reprod Med 2013; 11:939-944.

40. Lewis B, Aitken RJ. A redox-regulated tyrosine phosphorylation cascade in rat spermatozoa. J Androl  2001; 22:611-622.