Avanafil Mitigates Testicular Ischemia/Reperfusion Injury Via NLRP3 Pathway Modulation in Rats

Overview

Journal Reprod Sci

Publisher Springer

Specialty Reproductive Medicine

Date 2024 Sep 20

PMID 39302541

Authors

Muhammet Celik

Pelin Aydin

Maide Sena Civelek

Nurullah Akgun

Zeynep Karakoy

Cihad Ozcelik

Gulcin Tanriverdiyeva

Erdem Toktay

Affiliations

Soon will be listed here.

Abstract

Objective: In our study, the effectiveness of avanafil, a second-generation phosphodiesterase-5 (PDE5) inhibitor, on testicular torsion (TT) related ischemia/reperfusion injury via NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), which triggers inflammatory response, are studied molecularly, biochemically and histopathologically.

Material And Method: This study was performed on 24 male Wistar albino rats randomized into four groups. Testicular ischemia/reperfusion (I/R) model was created for groups 2, 3 and 4. Groups 3 and 4, respectively, were administered a dose of 5 and 10 mg/kg avanafil before reperfusion by gavage. The testicles which were left in ischemia for two hours, were detorsioned for four hours. All animals were sacrificed after reperfusion. Testicular tissues were examined molecularly, biochemically and histopathologically.

Results: The NLRP3, Interleukin-1β (IL-1β) and Tumor Necrosis alpha (TNF-α) mRNA expression levels were observed to be significantly increased in the I/R group compared to the healthy group (p < 0.001). After both doses of avanafil, NLRP3, IL-1β and TNF-α mRNA expression levels, which increased as a result of I/R, decreased in both avanafil groups. (p < 0.001). The greatest decrease was seen at the dose of 10 mg/kg (p < 0.001). Increased Malondialdehyde (MDA) levels due to I/R were statistically significantly decreased in both doses of avanafil (p < 0.001). Decreased Superoxide Dismutase (SOD) levels due to I/R damage increased statistically significantly in both doses of avanafil (p < 0.001).

Conclusion: It was found that avanafil can reduce the damage caused by testicular I/R and that it will find new applications in the future with the support of advanced experimental and clinical studies.

References

Moslemi M, Kamalimotlagh S . Evaluation of acute scrotum in our consecutive operated cases: a one-center study. Int J Gen Med. 2014; 7:75-8. PMC: 3896279. DOI: 10.2147/IJGM.S52413. View

Dokmeci D . Testicular torsion, oxidative stress and the role of antioxidant therapy. Folia Med (Plovdiv). 2007; 48(3-4):16-21. View

Makela E, Roine R, Taskinen S . Paternity, erectile function, and health-related quality of life in patients operated for pediatric testicular torsion. J Pediatr Urol. 2019; 16(1):44.e1-44.e4. DOI: 10.1016/j.jpurol.2019.10.008. View

Zhong L, Yang M, Zou X, Du T, Xu H, Sun J . Human umbilical cord multipotent mesenchymal stromal cells alleviate acute ischemia-reperfusion injury of spermatogenic cells via reducing inflammatory response and oxidative stress. Stem Cell Res Ther. 2020; 11(1):294. PMC: 7366899. DOI: 10.1186/s13287-020-01813-5. View

Jacobsen F, Rudlang T, Fode M, Ostergren P, Sonksen J, Ohl D . The Impact of Testicular Torsion on Testicular Function. World J Mens Health. 2019; 38(3):298-307. PMC: 7308234. DOI: 10.5534/wjmh.190037. View

Bender A, Beavo J . Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006; 58(3):488-520. DOI: 10.1124/pr.58.3.5. View

Das A, Durrant D, Salloum F, Xi L, Kukreja R . PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. Pharmacol Ther. 2014; 147:12-21. PMC: 4494657. DOI: 10.1016/j.pharmthera.2014.10.003. View

Xu Q, Zhao B, Ye Y, Li Y, Zhang Y, Xiong X . Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke. J Neuroinflammation. 2021; 18(1):123. PMC: 8166383. DOI: 10.1186/s12974-021-02137-8. View

Tavalaee M, Rahmani M, Drevet J, Nasr-Esfahani M . The NLRP3 inflammasome: molecular activation and regulation in spermatogenesis and male infertility; a systematic review. Basic Clin Androl. 2022; 32(1):8. PMC: 9150048. DOI: 10.1186/s12610-022-00157-9. View

10.

Antonuccio P, Micali A, Romeo C, Freni J, Vermiglio G, Puzzolo D . NLRP3 Inflammasome: A New Pharmacological Target for Reducing Testicular Damage Associated with Varicocele. Int J Mol Sci. 2021; 22(3). PMC: 7865407. DOI: 10.3390/ijms22031319. View

11.

Kose D, Kose A, Halici Z, Cadirci E, Tavaci T, Gurbuz M . Bosentan, a drug used in the treatment of pulmonary hypertension, can prevent development of osteoporosis. Iran J Basic Med Sci. 2021; 24(7):922-927. PMC: 8528255. DOI: 10.22038/ijbms.2021.54152.12172. View

12.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

13.

Ohkawa H, Ohishi N, Yagi K . Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979; 95(2):351-8. DOI: 10.1016/0003-2697(79)90738-3. View

14.

Wang H, Yuan J, Hu X, Tao K, Liu J, Hu D . The effectiveness and safety of avanafil for erectile dysfunction: a systematic review and meta-analysis. Curr Med Res Opin. 2014; 30(8):1565-71. DOI: 10.1185/03007995.2014.909391. View

15.

Palit V, Eardley I . An update on new oral PDE5 inhibitors for the treatment of erectile dysfunction. Nat Rev Urol. 2010; 7(11):603-9. DOI: 10.1038/nrurol.2010.165. View

16.

Mostafa T . Useful Implications of Low-dose Long-term Use of PDE-5 Inhibitors. Sex Med Rev. 2016; 4(3):270-284. DOI: 10.1016/j.sxmr.2015.12.005. View

17.

Shih P, Cheng C, Li H, Huang M, Chiu C, Chen J . Pretreatment with sildenafil alleviates early lung ischemia-reperfusion injury in a rat model. J Surg Res. 2013; 185(2):e77-83. DOI: 10.1016/j.jss.2013.07.010. View

18.

Koka S, Xi L, Kukreja R . Chronic inhibition of phosphodiesterase 5 with tadalafil affords cardioprotection in a mouse model of metabolic syndrome: role of nitric oxide. Mol Cell Biochem. 2020; 468(1-2):47-58. PMC: 10726535. DOI: 10.1007/s11010-020-03710-0. View

19.

Ozdegirmenci O, Kucukozkan T, Akdag E, Topal T, Haberal A, Kayir H . Effects of sildenafil and tadalafil on ischemia/reperfusion injury in fetal rat brain. J Matern Fetal Neonatal Med. 2010; 24(2):317-23. DOI: 10.3109/14767058.2010.492061. View

20.

Del Rio D, Stewart A, Pellegrini N . A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis. 2005; 15(4):316-28. DOI: 10.1016/j.numecd.2005.05.003. View