Resveratrol decreases apoptosis and NLRP3 complex expressions in experimental varicocele rat model

Document Type: Original Article


1 Department of Anatomy, School of Medicine, Arak University of Medical Sciences, Arak, Iran

2 Department of Genetics and Biochemistry, School of Medicine, Arak University of Medical Sciences, Arak, Iran

3 Department of Immunology and Microbiology, School of Medicine, Arak University of Medical Sciences, Arak, Iran

4 Department of Anatomy, School of Medicine, Giulan University of Medical Sciences, Rasht, Iran

5 Institute of Neuroanatomy, Medical Clinic, RWTH Aachen University, 52074 Aachen, Germany


Objective(s): Varicocele is an abnormal dilation in the testicular vein, which can cause hypoxia, reactive oxygen species accumulation, elevation in testicular temperature, and promote apoptosis and increase proinflammatory cytokine production. According to the varicocele pathophysiology, it is possible that a group of cytosolic receptors called nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes also involve in varicocele pathogenesis. Due to the important role of antioxidant in decreasing the testis tissue damage, in this study we investigated the protective effect of resveratrol (RES) on NLRP3 complex and apoptosis in experimental varicocele rats.
Materials and Methods: In this study, 40 male Wistar rats were randomly divided into 5 groups (8 rats in each group): Control, experimental left varicocele (ELV), ELV + ethanol, ELV + 20 mg/kg RES and ELV + 50 mg/kg RES. Varicocele was induced by partial ligation of the left renal vein. Three months after varicocele induction, RESwas orally administered to rats for 1 month. The expression levels of NLRP3, apoptosis associated speck-like protein (ASC), caspase-1, Bax and Bcl2 were analyzed using real time PCR.
Results: Our results showed that RESat both doses significantly (P≤ 0.05) decreased the gene expression levels of ASC, NLRP3, caspase-1 and Bax and increased Bcl2 gene expression at high dose.
Conclusions: RESby reducing inflammatory factors and decreasing apoptosis might be used as adjuvant therapy to reduce varicocele complication.


Main Subjects

1. Pasqualotto F, Agarwal A. Varicocele and male infertility: an evidence based review. Arch Med Sci 2009; 5:S20-27.

2. Galan J, De Felici M, Buch B, Rivero M, Segura A, Royo J, et al. Association of genetic markers within the KIT and KITLG genes with human male infertility. Hum Reprod 2006; 21:3185-3192.

3. Krishna Reddy S. Varicocele and Male Infertility: Current Issues in Management-A Review. Med Surg Urol 2014; 3:137-142

4. Sandlow J. Pathogenesis and treatment of varicoceles: Controversy still surrounds surgical treatment. BMJ 2004; 328:967-968.

5. Habibi B, Seifi B, Mougahi S-H, Ojaghi M, Sadeghipour H. Increases in interleukin-6 and interferon-gamma levels is progressive in immature rats with varicocele. Ir J Med Sci (1971-) 2015; 184:531-537.

6. Zedler S, Faist E. The impact of endogenous triggers on trauma-associated inflammation. Curr Opin Crit Care 2006; 12:595-601.

7. Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140:821-832.

8. Fu Y, Wang Y, Du L, Xu C, Cao J, Fan T, et al. Resveratrol inhibits ionising irradiation-induced inflammation in MSCs by activating SIRT1 and limiting NLRP-3 inflammasome activation. Int  J Mol Sci 2013; 14:14105-14118.

9. Latz E. The inflammasomes: mechanisms of activation and function. Curr Opin  Immunol 2010; 22:28-33.

10. Hedger MP, Meinhardt A. Cytokines and the immune-testicular axis. J Reprod Immunol 2003; 58:1-26.

11. Kefer JC, Agarwal A, Sabanegh E. Role of antioxidants in the treatment of male infertility. Int J Urol 2009; 16:449-457.

12. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J Clin Invest 2001; 107:135-142.

13. Mendes TB, Paccola CC, de Oliveira Neves FM, Simas JN, da Costa Vaz A, Cabral REL, et al. Resveratrol improves reproductive parameters of adult rats varicocelized in peripuberty. Reproduction 2016; 152:23-35.

14. Abdel-Dayem M. Histological and immunohistochemical changes in the adult rat testes after left experimental varicocele and possible protective effects of resveratrol. Egypt J Histol 2009; 32:81-90.

15. Turner T. The study of varicocele through the use of animal models. Hum Reprod Update 2001; 7:78-84.

16. Ku JH, Shim HB, Kim SW, Paick JS. The role of apoptosis in the pathogenesis of varicocele. BJU Int 2005; 96:1092-1096.

17. Schoor RA, Elhanbly SM, Niederberger CS. The pathophysiology of varicocele-associated male infertility. Curr Urol Rep 2001; 2:432-436.

18. Paduch DA, Skoog SJ. Current management of adolescent varicocele. Rev Urol 2001; 3:120-133.

19. Romeo C, Santoro G. Free radicals in adolescent varicocele testis. Oxid Med Cell Longev 2014; 2014.

20. Semercioz A, Onur R, Ogras S, Orhan I. Effects of melatonin on testicular tissue nitric oxide level and antioxidant enzyme activities in experimentally induced left varicocele. Neuro Endocrinol Lett 2003; 24:86-90.

21. Frémont L. Biological effects of resveratrol. Life Sci 2000; 66:663-673.

22. Fann DY-W, Lee S, Manzanero S, Tang S-C, Gelderblom M, Chunduri P, et al. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis 2013; 4:e790.

23. Zhang X, Ibrahim E, de Rivero Vaccari JP, Lotocki G, Aballa TC, Dietrich WD, et al. Involvement of the inflammasome in abnormal semen quality of men with spinal cord injury. Ferti Steril 2013; 99:118-124. e112.

24. Sulaiman M, Matta MJ, Sunderesan N, Gupta MP, Periasamy M, Gupta M. Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy. Am J Physiol Heart CircPhysiol2010; 298:H833-H843.

25. Sahin Z, Celik-Ozenci C, Akkoyunlu G, Korgun ET, Acar N, Erdogru T, et al. Increased expression of interleukin-1α and interleukin-1β is associated with experimental varicocele. Ferti Steril 2006; 85:1265-1275.

26. Nallella KP, Allamaneni SS, Pasqualotto FF, Sharma RK, Thomas AJ, Agarwal A. Relationship of interleukin-6 with semen characteristics and oxidative stress in patients with varicocele. Urology 2004; 64:1010-1013.

27. Kilinc F, Kayaselcuk F, Aygun C, Guvel S, Egilmez T, Ozkardes H. Experimental varicocele induces hypoxia inducible factor-1α, vascular endothelial growth factor expression and angiogenesis in the rat testis. J Urol 2004; 172:1188-1191.

28. Lee J-D, Jeng S-Y, Lee T-H. Increased expression of hypoxia-inducible factor-1α in the internal spermatic vein of patients with varicocele. J Urol 2006; 175:1045-1048.

29. Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol 2015; 6:262-270.

30. Liu C, Shi Z, Fan L, Zhang C, Wang K, Wang B. Resveratrol improves neuron protection and functional recovery in rat model of spinal cord injury. Brain Res 2011; 1374:100-109.

31. Ourique GM, Finamor IA, Saccol EM, Riffel AP, Pês TS, Gutierrez K, et al. Resveratrol improves sperm motility, prevents lipid peroxidation and enhances antioxidant defences in the testes of hyperthyroid rats. Rep Toxicol 2013; 37:31-39.

32. Chen C-J, Yu W, Fu Y-C, Wang X, Li J-L, Wang W. Resveratrol protects cardiomyocytes from hypoxia-induced apoptosis through the SIRT1–FoxO1 pathway. Biochem Biophys Res Commun 2009; 378:389-393.

33. Nicolini G, Rigolio R, Miloso M, Bertelli AA, Tredici G. Anti-apoptotic effect of trans-resveratrol on paclitaxel-induced apoptosis in the human neuroblastoma SH-SY5Y cell line. Neurosci Lett 2001; 302:41-44.