Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Efficacy of a novel water-soluble curcumin derivative versus sildenafil citrate in mediating erectile function

Abstract

The present study was conducted to assess the efficacy of a novel curcumin derivative (NCD) versus sildenafil citrate in erectile signaling. The study was conducted on 10 control male rats and 50 diabetic male rats divided into the following groups: diabetic, curcumin, NCD, sildenafil and NCD combined with sildenafil. Cavernous tissue (CC) gene expression levels of heme oxygenase (HO)-1, Nrf2, NF-κβ and p38, enzyme activities of HO and nitric oxide synthase (NOS), cyclic guanosine monophosphate (cGMP) and intracavernosal pressure (ICP) were assessed. Results showed that 12 weeks after induction of diabetes, erectile dysfunction was confirmed by the significant decrease in ICP, a significant decrease in cGMP, NOS, HO enzyme activities, a significant decrease in HO-1 gene and a significant elevation of NF-κβ, p38 genes. Administration of all therapeutic interventions led to a significant elevation in ICP, cGMP levels, a significant increase in HO-1 and NOS enzymes, a significant increase in HO-1 and Nrf2 gene expression, and a significant decrease in NF-κβ, p38 gene expression. NCD or its combination with sildenafil showed significant efficacy and more prolonged duration of action. In conclusion, NCD could enhance erectile function with more efficacy and more prolonged duration of action.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Abdel Aziz MT, El-Asmer MF, Mostafa T, Mostafa S, Atta H, Wassef MA et al. Heme oxygenase versus nitric oxide synthase in signaling mediating sildenafil citrate action. J Sex Med 2007; 4: 1098–1107.

    Article  CAS  Google Scholar 

  2. Abdel Aziz MT, Mostafa T, Atta H, Wassef MA, Fouad HH, Rashed LA et al. Putative role of carbon monoxide signaling pathway in penile erectile function. J Sex Med 2009; 6: 49–60.

    Article  CAS  Google Scholar 

  3. Hua W, Chen Q, Gong F, Xie C, Zhou S, Gao L . Cardioprotection of H2S by downregulating iNOS and upregulating HO-1 expression in mice with CVB3-induced myocarditis. Life Sci 2013; 93: 949–954.

    Article  CAS  Google Scholar 

  4. D'Araio E, Shaw N, Millward A, Demaine A, Whiteman M, Hodgkinson A . Hydrogen sulfide induces heme oxygenase-1 in human kidney cells. Acta Diabetol 2013; 51: 155–157.

    Article  Google Scholar 

  5. Abdel Aziz MT, Mostafa T, Atta H, Rashed L, Marzouk SA, Obaia EM et al. The role of PDE5 inhibitors in heme oxygenase-cGMP relationship in rat cavernous tissues. J Sex Med 2008; 5: 1636–1645.

    Article  CAS  Google Scholar 

  6. Andreadi CK, Howells LM, Atherfold PA, Manson MM . Involvement of Nrf2, p38, B-Raf, and nuclear factor-kappaB, but not phosphatidylinositol 3-kinase, in induction of heme oxygenase-1 by dietary polyphenols. Mol Pharmacol 2006; 69: 1033–1040.

    CAS  PubMed  Google Scholar 

  7. Zhao R, Yang B, Wang L, Xue P, Deng B, Zhang G et al. Curcumin protects human keratinocytes against inorganic arsenite-induced acute cytotoxicity through an NRF2-dependent mechanism. Oxid Med Cell Longev 2013; 2013: 412576.

    PubMed  PubMed Central  Google Scholar 

  8. Abdel Aziz MT, El Asmer MF, Rezq A, Kumosani TA, Mostafa S, Mostafa T et al. Novel water soluble curcumin derivative mediates erectile signaling. J Sex Med 2010; 7: 2714–2722.

    Article  CAS  Google Scholar 

  9. Gao S, Duan X, Wang X, Dong D, Liu D, Li X et al. Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion. Food Chem Toxicol 2013; 59: 739–747.

    Article  CAS  Google Scholar 

  10. Soetikno V, Sari FR, Lakshmanan AP, Arumugam S, Harima M, Suzuki K et al. Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keap1 pathway. Mol Nutr Food Res 2013; 57: 1649–1659.

    Article  CAS  Google Scholar 

  11. Hill-Kapturczak N, Thamilselvan V, Liu F, Nick HS, Agarwal A . Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells. Am J Physiol Renal Physiol 2001; 281: F851–F859.

    Article  CAS  Google Scholar 

  12. Xu PH, Long Y, Dai F, Liu ZL . The relaxant effect of curcumin on porcine coronary arterial ring segments. Vascul Pharmacol 2007; 47: 25–30.

    Article  CAS  Google Scholar 

  13. Schini-Kerth VB, Auger C, Étienne-Selloum N, Chataigneau T . Polyphenol-induced endothelium-dependent relaxations. Role of NO and EDHF. Adv Pharmacol 2010; 60: 136–175.

    Google Scholar 

  14. Subramani PA, Narala VR . Challenges of curcumin bioavailability: novel aerosol remedies. Nat Prod Commun 2013; 8: 121–124.

    CAS  PubMed  Google Scholar 

  15. Rezq AM, Abdel Aziz MT, Al-Malki AL Gelatin, a novel curcumin drug carrier system, WO/2011/100984. World Intellect Prop Org (WIPO) 2011, http://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid+90C05C7570FE02B89EBE9013FC25D794.wapp1?docId=WO2011100984&recNum=72&office=&queryString=&prevFilter=&sortOption=Pub+Date+Desc&maxRec=8021524.

  16. Hu J-J, Gu H-Y, Ding W-L, Yuan S-J, Zhong M-F, Liu L . Correlation between nNOS expression and erectile dysfunction in experimental diabetes mellitus rats of different ages. Neuroembryol Aging 2008; 5: 144–150.

    Article  CAS  Google Scholar 

  17. Li WJ, Zhou J, Li B, Wang H, Peng YB, Wang Z . PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats. J Sex Med 2011; 8: 1072–1082.

    Article  CAS  Google Scholar 

  18. Paget GE, Barnes GM . Evaluation of Drug Activities Vol. 1. Academic Press: London, 1964; 135.

    Book  Google Scholar 

  19. Abdel Aziz MT, Abraham N, Mostafa T, Mahfouz S, Atta H, Wassef MA et al. Heme oxygenase-1 (HO-1) gene transfer and CORM-3 as therapeutic modalities in erectile dysfunction. Andrologia 2008; 5: 363–343.

    Google Scholar 

  20. Moshag H, Kok B, Huizenga JR, Jansen LK . Nitrite and nitrate determination in plasma: a critical evaluation. Clin Chem 1995; 41: 892–896.

    Google Scholar 

  21. Abdel Aziz MT, Motawi T, Rezq A, Mostafa T, Fouad HH, Ahmed HH et al. Effects of a water-soluble curcumin protein conjugate vs. pure curcumin in a diabetic model of erectile dysfunction. J Sex Med 2012; 9: 1815–1833.

    Article  CAS  Google Scholar 

  22. Xia ZW, Zhou WP, Cui WJ, Zhang XH, Shen QX, Li YZ et al. Structure prediction and activity analysis of human heme oxygenase-1 and its mutant. World J Gastroenterol 2004; 10: 2352–2356.

    Article  CAS  Google Scholar 

  23. Mulhall JP, Verma N, Deveci S, Tal R, Kobylarz K, Müller A . Sildenafil citrate improves erectile function after castration in a rat model. BJU Int, 2013; 113: 656–661.

    Article  Google Scholar 

  24. Strong TD, Gebska MA, Burnett AL, Champion HC, Bivalacqua TJ . Endothelium-specific gene and stem cell-based therapy for erectile dysfunction. Asian J Androl 2008; 10: 14–22.

    Article  CAS  Google Scholar 

  25. Yang G, Lucas R, Caldwell R, Yao L, Romero MJ, Caldwell RW . Novel mechanisms of endothelial dysfunction in diabetes. J Cardiovasc Dis Res 2010; 1: 59–63.

    Article  Google Scholar 

  26. Xu J, Zou MH . Molecular insights and therapeutic targets for diabetic endothelial dysfunction. Circulation 2009; 120: 1266–1286.

    Article  Google Scholar 

  27. Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB . Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement. J Biol Chem 2003; 31: 28793–28798.

    Article  Google Scholar 

  28. Chen Z, Singer WD, Sternweis PC, Sprang SR . Structure of the p115RhoGEF rgRGS domain-Galpha13/i1 chimera complex suggests convergent evolution of a GTPase activator. Nat Struct Mol Biol 2005; 2: 191–197.

    Article  Google Scholar 

  29. Romero MJ, Platt DH, Tawfik HE, Labazi M, El-Remessy AB, Bartoli M et al. Diabetes-induced coronary vascular dysfunction involves increased arginase activity. Circ Res 2008; 1: 95–102.

    Article  Google Scholar 

  30. Zhang C . The role of inflammatory cytokines in endothelial dysfunction. Basic Res Cardiol 2008; 103: 398–406.

    Article  CAS  Google Scholar 

  31. Abdel Aziz MT, El Asmer MF, Mostafa T, Atta H, Mahfouz S, Fouad H et al. Effects of losartan, HO-1 inducers or HO-1 inhibitors on erectile signaling in diabetic rats. J Sex Med 2009; 6: 3254–3264.

    Article  CAS  Google Scholar 

  32. Hamed S, Brenner B, Roguin A . Nitric Oxide: a key factor behind the dysfunctionality of endothelial progenitor cells in diabetes mellitus type-2. Cardiovasc Res 2011; 91: 9–15.

    Article  CAS  Google Scholar 

  33. Wan ZH, Li WZ, Li YZ, Chen L, Li GH, Hu WF et al. Poly(ADP-Ribose) polymerase inhibition improves erectile function in diabetic rats. J Sex Med 2011; 8: 1002–1014.

    Article  CAS  Google Scholar 

  34. Rungseesantivanon S, Thenchaisri N, Ruangvejvorachai P, Patumraj S . Curcumin supplementation could improve diabetes-induced endothelial dysfunction associated with decreased vascular superoxide production and PKC inhibition. BMC Complement Altern Med 2010; 10: 57.

    Article  Google Scholar 

  35. Usharani P, Mateen A, Naidu M, Raju Y, Chandra N . Effect of NCB-02, Atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with T2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study. Drug R D 2008; 9: 243–250.

    Article  CAS  Google Scholar 

  36. Ahmad M, Turkseven S, Mingone CJ, Gupte SA, Wolin MS, Abraham NG . Heme oxygenase-1 gene expression increases vascular relaxation and decreases inducible nitric oxide synthase in diabetic rats. Cell Mol Biol 2005; 51: 371–376.

    CAS  PubMed  Google Scholar 

  37. Ryter SW, Otterbein LE, Morse D, Choi AM . Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. Mol Cell Biochem 2002; 234–235: 249–263.

    Article  Google Scholar 

  38. Shamloul R . The potential role of the heme oxygenase/carbon monoxide system in male sexual dysfunctions. J Sex Med 2009; 6: 324–333.

    Article  CAS  Google Scholar 

  39. Aggarwal BB, Sung B . Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 2009; 30: 85–94.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H H Fouad.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on International Journal of Impotence Research website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zaahkouk, A., Abdel Aziz, M., Rezq, A. et al. Efficacy of a novel water-soluble curcumin derivative versus sildenafil citrate in mediating erectile function. Int J Impot Res 27, 9–15 (2015). https://doi.org/10.1038/ijir.2014.24

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijir.2014.24

This article is cited by

Search

Quick links