The Effects of N-Acetylcysteine on MMP-2 and MMP-9 Immune Activities in Testicular Tissue of Streptezotocin Induced Diabetic Rats

Year 2019, Volume: 9 Issue: 1, 59 - 67, 20.03.2019

Alper Yalcın

https://doi.org/10.31832/smj.492802

Cited By: 3

Abstract

Objective: This study was performed to investigate
the effects of N-Acetylcysteine (NAC) on matrix metalloproteinases (Mmp-2 and
Mmp-9) immunoreactivity in testicular tissue of diabetic rats.

Materials and Methods: 28 male
rats were allocated into four groups n (7); No treatment was applied to Control
group. Diabetes was induced upon injection of a single dose streptozocin 50
mg/kg intraperitoneally on diabetes group (DM). N-Acetylcysteine group (NAC) and
following  diabetes development, Diabetic
+ NAC groups were treated with i.p.100 mg/kg NAC daily. Oxidative damage was
evaluated with Total Antioxidant Status (TAS) and Total Oxidant Status (TOS)
activities while the testicular damage was determined by histopathological evaluation
and immunohistochemical assessment of MMP-2 and MMP-9 at the testicular
tissues.

Results: TAS
levels were found to be increased in diabetic NAC-treated group animals
whereas  TOS, MMP-2 and MMP-9 levels were
decreased in the same group. For the histological findings, there were no
testicular changes In
the NAC alone control group whereas the alterations such as marked degeneration,
vacuole formation and basement membrane thickening of tubules seminiferus
contortus were observed in the testicular tissues of the DM group. But, in the
treatment group DM+NAC, these alterations were found to be comparatively
decreased.

Conclusion:  Our findings suggest that administration of
NAC minimize testicular damage in diabetic rats and might be a potential
candidate to reduce/eliminate the negative effects of diabetes on the
testicular tissue.

Keywords

N-acetylcysteine (NAC), Mmp2, Mmp9, Testes, Diabetes

References

• 1. Agbaje IM, Rogers DA, McVicar CM, McClure N, Atkinson AB, Mallidis C, et al. Insulin dependant diabetes mellitus: implications for male reproductive function. Hum Reprod Oxf Engl 2007;22:1871–1877.2. Hasselbaink DM, Glatz JFC, Luiken JJFP, Roemen THM, Van der Vusse GJ. Ketone bodies disturb fatty acid handling in isolated cardiomyocytes derived from control and diabetic rats. Biochem J 2003;371:753–760.3. Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson A. Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am J Clin Nutr 1977;30:531–538.4. Das A, McGuire PG, Eriqat C, Ober RR, DeJuan E, Williams GA, et al. Human diabetic neovascular membranes contain high levels of urokinase and metalloproteinase enzymes. Invest Ophthalmol Vis Sci 1999;40:809–813.5. Mallidis C, Agbaje IM, Rogers DA, Glenn JV, Pringle R, Atkinson AB, et al. Advanced glycation end products accumulate in the reproductive tract of men with diabetes. Int J Androl 2009;32:295–305.6. Melendez-Ramirez LY, Richards RJ, Cefalu WT. Complications of type 1 diabetes. Endocrinol Metab Clin North Am 2010;39:625–640.7. Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 1994;331:1428–1436.8. Ficher M, Zuckerman M, Fishkin RE, Goldman A, Neeb M, Fink PJ, et al. Do endocrines play an etiological role in diabetic and nondiabetic sexual dysfunctions? J Androl 1984;5:8–16.9. Steger RW, Rabe MB. The effect of diabetes mellitus on endocrine and reproductive function. Proc Soc Exp Biol Med Soc Exp Biol Med N Y N 1997;214:1–11.10. Jangir RN, Jain GC. Diabetes mellitus induced impairment of male reproductive functions: a review. Curr Diabetes Rev 2014;10:147–157.11. Mital P, Hinton BT, Dufour JM. The blood-testis and blood-epididymis barriers are more than just their tight junctions. Biol Reprod 2011;84:851–858.12. Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 2000;14:2123–2133.13. Longin J, Le Magueresse-Battistoni B. Evidence that MMP-2 and TIMP-2 are at play in the FSH-induced changes in Sertoli cells. Mol Cell Endocrinol 2002;189:25–35.14. Siu MKY, Lee WM, Cheng CY. The interplay of collagen IV, tumor necrosis factor-alpha, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis. Endocrinology 2003;144:371–387.15. Fritz IB, Tung M, Ailenberg M. Proteases and antiproteases in the seminiferous tubules. In: Russell LD, Griswold MD (eds.). The Sertoli Cell. Clearwater, FL: Cache River Press, 1993. p.217–235.16. Skinner MK. Cell-cell interactions in the testis. Endocr Rev 1991;12:45–77.17. La Vignera S, Condorelli R, Vicari E, D’Agata R, Calogero AE. Diabetes mellitus and sperm parameters. J Androl 2012;33:145–153.18. Amaral S, Oliveira PJ, Ramalho-Santos J. Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev 2008;4:46–54.19. Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996;19:257–267.20. Karimi J, Goodarzi MT, Tavilani H, Khodadadi I, Amiri I. Relationship between advanced glycation end products and increased lipid peroxidation in semen of diabetic men. Diabetes Res Clin Pract 2011;91:61–66.21. Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int Suppl 2000;77:S26-30.22. Piconi L, Quagliaro L, Ceriello A. Oxidative stress in diabetes. Clin Chem Lab Med 2003;41:1144–1149.23. Wiernsperger NF. Oxidative stress as a therapeutic target in diabetes: revisiting the controversy. Diabetes Metab 2003;29:579–585.24. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827–839.25. Alves MG, Martins AD, Cavaco JE, Socorro S, Oliveira PF. Diabetes, insulin-mediated glucose metabolism and Sertoli/blood-testis barrier function. Tissue Barriers 2013;1:e23992.26. Hurst GA, Shaw PB, LeMaistre CA. Laboratory and clinical evaluation of the mucolytic properties of acetylcysteine. Am Rev Respir Dis 1967;96:962–970.27. Gibson KR, Neilson IL, Barrett F, Winterburn TJ, Sharma S, MacRury SM, et al. Evaluation of the Antioxidant Properties of N-acetylcysteine in Human Platelets: Prerequisite for Bioconversion to Glutathione for Antioxidant and Antiplatelet Activity: J Cardiovasc Pharmacol 2009;54:319–326.28. Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992;43:667–669.29. Ho E, Chen G, Bray TM. Supplementation of N-acetylcysteine inhibits NFκB activation and protects against alloxan-induced diabetes in CD-1 mice. FASEB J 1999;13:1845–1854.30. Kaneto H, Kajimoto Y, Miyagawa J, Matsuoka T, Fujitani Y, Umayahara Y, et al. Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. Diabetes 1999;48:2398–2406.31. Masha A, Brocato L, Dinatale S, Mascia C, Biasi F, Martina V. N-acetylcysteine is able to reduce the oxidation status and the endothelial activation after a high-glucose content meal in patients with Type 2 diabetes mellitus. J Endocrinol Invest 2009;32:352–356.32. Xia Z, Liu M, Wu Y, Sharma V, Luo T, Ouyang J, et al. N-acetylcysteine attenuates TNF-α-induced human vascular endothelial cell apoptosis and restores eNOS expression. Eur J Pharmacol 2006;550:134–142.33. Rigotti A, Miettinen HE, Krieger M. The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues. Endocr Rev 2003;24:357–387.34. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014;141:150–159.35. Samuni Y, Goldstein S, Dean OM, Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta 1830;2013:4117–4129.36. Mohasseb M, Ebied S, Yehia MAH, Hussein N. Testicular oxidative damage and role of combined antioxidant supplementation in experimental diabetic rats. J Physiol Biochem 2011;67:185–194.37. Rahimi R, Nikfar S, Larijani B, Abdollahi M. A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother Biomedecine Pharmacother 2005;59:365–373.38. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37:277–285.39. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103–1111.40. Russell LD, Peterson RN. Sertoli cell junctions: morphological and functional correlates. Int Rev Cytol 1985;94:177–211.41. Yao P-L, Lin Y-C, Richburg JH. Mono-(2-ethylhexyl) phthalate-induced disruption of junctional complexes in the seminiferous epithelium of the rodent testis is mediated by MMP2. Biol Reprod 2010;82:516–527.42. Yao P-L, Lin Y-C, Richburg JH. TNF alpha-mediated disruption of spermatogenesis in response to Sertoli cell injury in rodents is partially regulated by MMP2. Biol Reprod 2009;80:581–589.43. Gray KJ, Engelmann UH, Johnson EH, Fishman IJ. Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (Cytoxan) therapy. J Urol 1986;136:497–500.44. Lui W-Y, Lee WM. Molecular mechanisms by which hormones and cytokines regulate cell junction dynamics in the testis. J Mol Endocrinol 2009;43:43–51.45. Navaratna D, McGuire PG, Menicucci G, Das A. Proteolytic degradation of VE-cadherin alters the blood-retinal barrier in diabetes. Diabetes 2007;56:2380–2387.46. Reijerkerk A, Kooij G, van der Pol SMA, Khazen S, Dijkstra CD, de Vries HE. Diapedesis of monocytes is associated with MMP-mediated occludin disappearance in brain endothelial cells. FASEB J Off Publ Fed Am Soc Exp Biol 2006;20:2550–2552.47. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 2007;27:697–709.48. Warinrak C, Wu J-T, Hsu W-L, Liao J-W, Chang S-C, Cheng F-P. Expression of matrix metalloproteinases (MMP-2, MMP-9) and their inhibitors (TIMP-1, TIMP-2) in canine testis, epididymis and semen. Reprod Domest Anim Zuchthyg 2015;50:48–57.49. Longin J, Guillaumot P, Chauvin MA, Morera AM, Le Magueresse-Battistoni B. MT1-MMP in rat testicular development and the control of Sertoli cell proMMP-2 activation. J Cell Sci 2001;114:2125–2134.50. Chen H, Lam Fok K, Jiang X, Chan HC. New insights into germ cell migration and survival/apoptosis in spermatogenesis: Lessons from CD147. Spermatogenesis 2012;2:264–272.51. Barone R, Pitruzzella A, Marino Gammazza A, Rappa F, Salerno M, Barone F, et al. Nandrolone decanoate interferes with testosterone biosynthesis altering blood-testis barrier components. J Cell Mol Med 2017;21:1636–1647.52. Siu MKY, Cheng CY. Interactions of proteases, protease inhibitors, and the beta1 integrin/laminin gamma3 protein complex in the regulation of ectoplasmic specialization dynamics in the rat testis. Biol Reprod 2004;70:945–964.53. Maxwell PR, Timms PM, Chandran S, Gordon D. Peripheral blood level alterations of TIMP-1, MMP-2 and MMP-9 in patients with type 1 diabetes. Diabet Med J Br Diabet Assoc 2001;18:777–780.54. Zhang Q, Liu H-R, Ying H-J, Dai D-Z, Tang X-Y, Dai Y. Strontium fructose 1,6-diphosphate alleviates early diabetic testopathy by suppressing abnormal testicular matrix metalloproteinase system in streptozocin-treated rats. J Pharm Pharmacol 2009;61:229–236.55. Mallidis C, Agbaje I, Rogers D, Glenn J, McCullough S, Atkinson AB, et al. Distribution of the receptor for advanced glycation end products in the human male reproductive tract: prevalence in men with diabetes mellitus. Hum Reprod Oxf Engl 2007;22:2169–2177.56. Tang X-Y, Zhang Q, Dai D-Z, Ying H-J, Wang Q-J, Dai Y. Effects of strontium fructose 1,6-diphosphate on expression of apoptosis-related genes and oxidative stress in testes of diabetic rats. Int J Urol Off J Jpn Urol Assoc 2008;15:251–256.