Advertisement

Archives of Pharmacal Research

, Volume 39, Issue 12, pp 1693–1702 | Cite as

Carvedilol alleviates testicular and spermatological damage induced by cisplatin in rats via modulation of oxidative stress and inflammation

  • Ahmed H. Eid
  • Noha F. AbdelkaderEmail author
  • Ola M. Abd El-Raouf
  • Hala M. Fawzy
  • Ezz-El-Din S. El-Denshary
Research Article
First Online:

Abstract

The clinical application of the anticancer drug cisplatin is limited by its deleterious side effects, including male reproductive toxicity. In this context, the potential protective effect of carvedilol on testicular and spermatological damage induced by cisplatin in male Sprague–Dawley rats was investigated. Carvedilol was orally administered at a dose of 10 mg/kg for 2 weeks, and cisplatin was given as a single intraperitoneal injection of 10 mg/kg on the 12th day to induce toxicity. Cisplatin significantly reduced reproductive organ weight, sperm count and sperm motility, and increased sperm abnormalities and histopathological damage of testicular tissue. In addition, it resulted in a significant decline in serum testosterone as well as levels of testicular enzymatic and non-enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxides, and reduced glutathione). Moreover, cisplatin remarkably augmented malondialdehyde, nitric oxide, tumor necrosis factor-α, and nuclear factor-kappa B contents in testicular tissue. Conversely, carvedilol administration markedly mitigated cisplatin-induced testicular and spermatological injury as demonstrated by suppression of oxidative/nitrosative and inflammatory burden, amendment of antioxidant defenses, enhancement of steroidogenesis and spermatogenesis, and mitigation of testicular histopathological damage. The current study reveals a promising protective action of carvedilol against cisplatin-induced reproductive toxicity by virtue of its anti-inflammatory and antioxidant properties.

Keywords

Cisplatin Testicular damage Carvedilol Oxidative stress Inflammation 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The authors are grateful to Prof. Dr. Bakeir A and Prof. Dr. Ahmed KA (Department of Histology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt) for performing the histopathological and immunohistochemical examinations.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

References

  1. Adejuwon SA, Femi-Akinlosotu OM, Omirinde JO (2015) Cisplatin-induced testicular dysfunction and its amelioration by Launaea taraxacifolia leaf extract. Andrologia 47:553–559CrossRefPubMedGoogle Scholar
  2. Ahmed LA, Shehata NI, Abdelkader NF, Khattab MM (2014) Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice. PLoS One 9:e108889CrossRefPubMedPubMedCentralGoogle Scholar
  3. Aitken RJ, Curry BJ (2011) Redox regulation of human sperm function: from the physiological control of sperm capacitation to the etiology of infertility and DNA damage in the germ line. Antioxid Redox Signal 14:367–381CrossRefPubMedGoogle Scholar
  4. Alfieri AB, Briceno L, Fragasso G, Spoladore R, Palloshi A, Bassanelli G, Montano C, Arioli F, Cuko A, Ruotolo G, Margonato A (2008) Differential long-term effects of carvedilol on proinflammatory and antiinflammatory cytokines, asymmetric dimethylarginine, and left ventricular function in patients with heart failure. J Cardiovasc Pharmacol 52:49–54CrossRefPubMedGoogle Scholar
  5. Almaghrabi OA (2015) Molecular and biochemical investigations on the effect of quercetin on oxidative stress induced by cisplatin in rat kidney. Saudi J Biol Sci 22:227–231CrossRefPubMedGoogle Scholar
  6. Amin A, Hamza AA, Kambal A, Daoud S (2008) Herbal extracts counteract cisplatin-mediated cell death in rat testis. Asian J Androl 10:291–297CrossRefPubMedGoogle Scholar
  7. Amin A, Abraham C, Hamza AA, Abdalla ZA, Al-Shamsi SB, Harethi SS, Daoud S (2012) A standardized extract of Ginkgo biloba neutralizes cisplatin-mediated reproductive toxicity in rats. J Biomed Biotechnol. doi: 10.1155/2012/362049
  8. Arab HH, El-Sawalhi MM (2013) Carvedilol alleviates adjuvant-induced arthritis and subcutaneous air pouch edema: modulation of oxidative stress and inflammatory mediators. Toxicol Appl Pharmacol 268:241–248CrossRefPubMedGoogle Scholar
  9. Arozal W, Watanabe K, Veeraveedu PT, Ma M, Thandavarayan RA, Sukumaran V, Suzuki K, Kodama M, Aizawa Y (2010) Protective effect of carvedilol on daunorubicin-induced cardiotoxicity and nephrotoxicity in rats. Toxicol 274:18–26CrossRefGoogle Scholar
  10. Atessahin A, Sahna E, Turk G, Ceribasi AO, Yilmaz S, Yuce A, Bulmus O (2006) Chemoprotective effect of melatonin against cisplatin-induced testicular toxicity in rats. J Pineal Res 41:21–27CrossRefPubMedGoogle Scholar
  11. Bearden HJ, Fluquary J (1980) Applied animal reproduction. Restore Publishing Co. Inc., RestonGoogle Scholar
  12. Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888PubMedGoogle Scholar
  13. Beytur A, Ciftci O, Oguz F, Oguzturk H, Yilmaz F (2012) Montelukast attenuates side effects of cisplatin including testicular, spermatological, and hormonal damage in male rats. Cancer Chemother Pharmacol 69:207–213CrossRefPubMedGoogle Scholar
  14. Boekelheide K (2005) Mechanisms of toxic damage to spermatogenesis. J Natl Cancer Inst Monogr 34:6–8CrossRefGoogle Scholar
  15. Bubici C, Papa S, Dean K, Franzoso G (2006) Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance. Oncog 25:6731–6748CrossRefGoogle Scholar
  16. Carvalho Rodrigues MA, Silva Faria MC, Santos NA, Gobe GC, Dos Santos AC (2013) Carvedilol efficiently protects kidneys without affecting the antitumor efficacy of cisplatin in mice. Chem Biol Interact 206:90–99CrossRefPubMedGoogle Scholar
  17. Chirino YI, Pedraza-Chaverri J (2009) Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol 61:223–242CrossRefPubMedGoogle Scholar
  18. Ciftci O, Cetin A, Aydin M, Kaya K, Oguz F (2014) Fish oil, contained in eicosapentaenoic acid and docosahexaenoic acid, attenuates testicular and spermatological damage induced by cisplatin in rats. Andrologia 46:1161–1168CrossRefPubMedGoogle Scholar
  19. Dandona P, Ghanim H, Brooks DP (2007) Antioxidant activity of carvedilol in cardiovascular disease. J Hypertens 25:731–741CrossRefPubMedGoogle Scholar
  20. Erdinçler DS, Seven A, Inci F, Beǧer T, Candan G (1997) Lipid peroxidation and oxidant status in experimental animals: effect of aging and hypercholestrolemic diet. Clin Chim Acta 265:77–84CrossRefPubMedGoogle Scholar
  21. Fung C, Vaughn DJ (2011) Complications associated with chemotherapy in testicular cancer management. Nat Rev Urol 8:213–222CrossRefPubMedGoogle Scholar
  22. Hamdy N, El-Demerdash E (2012) New therapeutic aspect for carvedilol: antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage. Toxicol Appl Pharmacol 261:292–299CrossRefPubMedGoogle Scholar
  23. Hamza AA, Elwy HM, Badawi AM (2016) Fenugreek seed extract attenuates cisplatin-induced testicular damage in Wistar rats. Andrologia 48:211–221CrossRefPubMedGoogle Scholar
  24. Hayashi T, De Velasco MA, Saitou Y, Nose K, Nishioka T, Ishii T, Uemura H (2010) Carvedilol protects tubular epithelial cells from ischemia–reperfusion injury by inhibiting oxidative stress. Int J Urol 17:989–995CrossRefPubMedGoogle Scholar
  25. Ilbey YO, Ozbek E, Simsek A, Otunctemur A, Cekmen M, Somay A (2009) Potential chemoprotective effect of melatonin in cyclophosphamide- and cisplatin-induced testicular damage in rats. Fertil Steril 92:1124–1132CrossRefPubMedGoogle Scholar
  26. Kawai Y, Nakao T, Kunimura N, Kohda Y, Gemba M (2006) Relationship of intracellular calcium and oxygen radicals to Cisplatin-related renal cell injury. J Pharmacol Sci 100:65–72CrossRefPubMedGoogle Scholar
  27. Kaya K, Ciftci O, Cetin A, Dogan H, Basak N (2015) Hesperidin protects testicular and spermatological damages induced by cisplatin in rats. Andrologia 47:793–800CrossRefPubMedGoogle Scholar
  28. Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7:573–584CrossRefPubMedGoogle Scholar
  29. Khan MA, Liu J, Kumar G, Skapek SX, Falck JR, Imig JD (2013) Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity. FASEB J 27:2946–2956CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kleinert H, Pautz A, Linker K, Schwarz PM (2004) Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 500:255–266CrossRefPubMedGoogle Scholar
  31. Kumar A, Dogra S (2009) Neuroprotective effect of carvedilol, an adrenergic antagonist against colchicine induced cognitive impairment and oxidative damage in rat. Pharmacol Biochem Behav 92:25–31CrossRefPubMedGoogle Scholar
  32. Lin P-Y, Shen H-C, Chen C-J, Wu S-E, Kao H-L, Huang J-H, Wang D, Chen S-C (2010) The inhibition in tumor necrosis factor-α-induced attenuation in endothelial thrombomodulin expression by carvedilol is mediated by nuclear factor-κB and reactive oxygen species. J Thromb Thrombolysis 29:52–59CrossRefPubMedGoogle Scholar
  33. Longo V, Gervasi PG, Lubrano V (2011) Cisplatin induced toxicity in rat tissues: the protective effect of Lisosan G. Food Chem Toxicol 49:233–237CrossRefPubMedGoogle Scholar
  34. Migliavacca E, Ancerewicz J, Carrupt P-A, Testa B (1998) Theoretical parameters to characterize antioxidants. Part 2. The cases of melatonin and carvedilol. Helv Chim Acta 81:1337–1348CrossRefGoogle Scholar
  35. Naidu PS, Singh A, Kulkarni SK (2002) Carvedilol attenuates neuroleptic-induced orofacial dyskinesia: possible antioxidant mechanisms. Br J Pharmacol 136:193–200CrossRefPubMedPubMedCentralGoogle Scholar
  36. Nakayama K, Milbourne A, Schover LR, Champlin RE, Ueno NT (2008) Gonadal failure after treatment of hematologic malignancies: from recognition to management for health-care providers. Nat Clin Pract Oncol 5:78–89CrossRefPubMedGoogle Scholar
  37. Oliveira PJ, Bjork JA, Santos MS, Leino RL, Froberg MK, Moreno AJ, Wallace KB (2004) Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 200:159–168CrossRefPubMedGoogle Scholar
  38. Parlaktas BS, Atilgan D, Gencten Y, Akbas A, Markoc F, Erdemir F, Ozyurt H, Uluocak N (2014) The effects of carvedilol on ischemia-reperfusion injury in the rat testis. Int Braz J Urol 40:109–117PubMedGoogle Scholar
  39. Ramzy MM, El-Sheikh AA, Kamel MY, Abdelwahab SA, Morsy MA (2014) Mechanism of testicular protection of carvedilol in streptozotocin-induced diabetic rats. Indian J Pharmacol 46:161–165CrossRefPubMedPubMedCentralGoogle Scholar
  40. Rezvanfar MA, Rezvanfar MA, Shahverdi AR, Ahmadi A, Baeeri M, Mohammadirad A, Abdollahi M (2013) Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles. Toxicol Appl Pharmacol 266:356–365CrossRefPubMedGoogle Scholar
  41. Rodrigues MA, Rodrigues JL, Martins NM, Barbosa F, Curti C, Santos NA, Santos AC (2011) Carvedilol protects against cisplatin-induced oxidative stress, redox state unbalance and apoptosis in rat kidney mitochondria. Chem Biol Interact 189:45–51CrossRefPubMedGoogle Scholar
  42. Sahu BD, Koneru M, Bijargi SR, Kota A, Sistla R (2014) Chromium-induced nephrotoxicity and ameliorative effect of carvedilol in rats: involvement of oxidative stress, apoptosis and inflammation. Chem Biol Interact 223C:69–79CrossRefGoogle Scholar
  43. Salem EA, Salem NA, Maarouf AM, Serefoglu EC, Hellstrom WJ (2012) Selenium and lycopene attenuate cisplatin-induced testicular toxicity associated with oxidative stress in Wistar rats. Urology 79:1184.e1–1184.e6Google Scholar
  44. Sari FR, Arozal W, Watanabe K, Harima M, Veeravedu PT, Thandavarayan RA, Suzuki K, Arumugam S, Soetikno V, Kodama M (2011) Carvedilol attenuates inflammatory-mediated cardiotoxicity in daunorubicin-induced rats. Pharmaceuticals 4:551–566CrossRefPubMedCentralGoogle Scholar
  45. Savoia C, Schiffrin EL (2007) Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci 112:375–384CrossRefPubMedGoogle Scholar
  46. Sherif IO, Abdel-Aziz A, Sarhan OM (2014) Cisplatin-induced testicular toxicity in rats: the protective effect of arjunolic acid. J Biochem Mol Toxicol 28:515–521CrossRefPubMedGoogle Scholar
  47. Stahl O, Eberhard J, Jepson K, Spano M, Cwikiel M, Cavallin-Stahl E, Giwercman A (2006) Sperm DNA integrity in testicular cancer patients. Hum Reprod 21:3199–3205CrossRefPubMedGoogle Scholar
  48. Tak PP, Firestein GS (2001) NF-kappa B: a key role in inflammatory diseases. J Clin Invest 107:7–11CrossRefPubMedPubMedCentralGoogle Scholar
  49. Todd RC, Lippard SJ (2009) Inhibition of transcription by platinum antitumor compounds. Metallomics 1:280–291CrossRefPubMedPubMedCentralGoogle Scholar
  50. Tomao F, Miele E, Spinelli G, Tomao S (2006) Anticancer treatment and fertility effects. Literature review. J Exp Clin Cancer Res 25:475–481PubMedGoogle Scholar
  51. Wilop S, Von Hobe S, Crysandt M, Esser A, Osieka R, Jost E (2009) Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. J Cancer Res Clin Oncol 135:1429–1435CrossRefPubMedGoogle Scholar
  52. Yang SP, Ho LJ, Lin YL, Cheng SM, Tsao TP, Chang DM, Hsu YL, Shih CY, Juan TY, Lai JH (2003) Carvedilol, a new antioxidative beta-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-kappaB activity. Cardiovasc Res 59:776–787CrossRefPubMedGoogle Scholar
  53. Yao X, Panichpisal K, Kurtzman N, Nugent K (2007) Cisplatin nephrotoxicity: a review. Am J Med Sci 334:115–124CrossRefPubMedGoogle Scholar
  54. Yue TL, Cheng HY, Lysko PG, Mckenna PJ, Feuerstein R, Gu JL, Lysko KA, Davis LL, Feuerstein G (1992) Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 263:92–98PubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2016

Authors and Affiliations

  1. 1.Department of PharmacologyNational Organization for Drug Control and Research (NODCAR)GizaEgypt
  2. 2.Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt

Personalised recommendations

Cite article

Buy options