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Inhibitory effects of topical cyclosporine A 0.05 % on immune-mediated corneal neovascularization in rabbits

  • Yasin Yücel Bucak
  • Mesut ErdurmusEmail author
  • Elçin Hakan Terzi
  • Aysel Kükner
  • Serdal Çelebi
Basic Science

Abstract

Background

We aimed to study the inhibitory effects of topical cyclosporine A (CsA) 0.05 % on immune-mediated corneal neovascularization, and to compare its efficacy with those of dexamethasone 0.1 % and bevacizumab 0.5 %.

Methods

Immune-mediated corneal neovascularization was created in 36 right eyes of 36 rabbits. The rabbits were then randomized into four groups. Group I received CsA 0.05 %, Group II received dexamethasone 0.1 %, Group III received bevacizumab 0.5 %, and Group IV received isotonic saline twice a day for 14 days. The corneal surface covered with neovascular vessels was measured on the photographs. The rabbits were then sacrificed and the corneas excised. Paraffin-embedded sections were stained with hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay.

Results

The means of percent area of corneal neovascularization in Group I, II, III, and IV were 24.4 %, 5.9 %, 37.1 %, and 44.1 %, respectively. The inhibitory effect of CsA 0.05 % was found to be better than the effect found in the bevacizumab 0.5 % and control groups (p = 0.03 and p = 0.02, respectively). CsA 0.05 % was found to have significantly lesser inhibitory effects on corneal neovascularization than dexamethasone 0.1 % (p < 0.001). Apoptotic cell density was higher in Group III and Group IV than in Group I and Group II. There was no difference between Group I and Group II in terms of apoptotic cell density (p = 0.7).

Conclusions

Topical CsA 0.05 % was shown to have an inhibitory effect on immune-mediated corneal neovascularization in rabbits.

Keywords

Arthus reaction Cyclosporine A Dexamethasone Bevacizumab Corneal neovascularization 

Notes

Acknowledgments

Competing interests, Funding

None of the authors has any competing financial interests in this study. This study supported by Abant Izzet Baysal University Scientific Research Committee (Project number: 2011.08.02.388).

References

  1. 1.
    Prabhasawat P, Tesavibul N, Mahawong W (2012) A randomized double-masked study of 0.05% cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction. Cornea 31:1386–9133PubMedCrossRefGoogle Scholar
  2. 2.
    Schechter BA, Katz RS, Friedman LS (2009) Efficacy of topical cyclosporine for the treatment of ocular rosacea. Adv Ther 26:651–659PubMedCrossRefGoogle Scholar
  3. 3.
    Salib GM, McDonald MB, Smolek M (2006) Safety and efficacy of cyclosporine 0.05% drops versus unpreserved artificial tears in dry-eye patients having laser in situ keratomileusis. J Cataract Refract Surg 32:772–728PubMedCrossRefGoogle Scholar
  4. 4.
    Hingorani M, Moodaley L, Calder VL, Buckley RJ, Lightman S (1998) A randomized, placebo-controlled trial of topical cyclosporin A in steroid-dependent atopic keratoconjunctivitis. Ophthalmology 105:1715–1720PubMedCrossRefGoogle Scholar
  5. 5.
    Poon A, Constantinou M, Lamoureux E, Taylor HR (2008) Topical Cyclosporin A in the treatment of acute graft rejection: a randomized controlled trial. Clin Exp Ophthalmol 36:415–421Google Scholar
  6. 6.
    Rao SN, Rao RD (2006) Efficacy of topical cyclosporine 0.05% in the treatment of dry eye associated with graft versus host disease. Cornea 25:674–678PubMedCrossRefGoogle Scholar
  7. 7.
    Okumus S, Coskun E, Tatar MG, Kaydu E, Yayuspayi R, Comez A, Erbagci I, Gurler B (2012) Cyclosporine a 0.05% eye drops for the treatment of subepithelial infiltrates after epidemic keratoconjunctivitis. BMC Ophthalmol 12:42PubMedCrossRefGoogle Scholar
  8. 8.
    Williams KA, Coster DJ (2007) The immunobiology of corneal transplantation. Transplantation 84:806–813PubMedCrossRefGoogle Scholar
  9. 9.
    Liu Y, Jiang J, Xiao H, Wang X, Li Y, Gong Y, Wang D, Huang Y (2012) Topical application of FTY720 and cyclosporin A prolong corneal graft survival in mice. Mol Vis 18:624–633PubMedGoogle Scholar
  10. 10.
    Hernández GL, Volpert OV, Iñiguez MA, Lorenzo E, Martínez-Martínez S, Grau R, Fresno M, Redondo JM (2001) Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J Exp Med 193:607–620PubMedCrossRefGoogle Scholar
  11. 11.
    Benelli U, Ross JR, Nardi M, Klintworth GK (1997) Corneal neovascularization induced by xenografts or chemical cautery. Inhibition by cyclosporin A. Invest Ophthalmol Vis Sci 38:274–282PubMedGoogle Scholar
  12. 12.
    Saita N, Fujiwara N, Yano I, Soejima K, Kobayashi K (2000) Trehalose 6,6′-dimycolate (cord factor) of Mycobacterium tuberculosis induces corneal angiogenesis in rats. Infect Immun 68:5991–5997PubMedCrossRefGoogle Scholar
  13. 13.
    Peebo BB, Fagerholm P, Traneus-Röckert C, Lagali N (2011) Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model. Angiogenesis 14:393–405PubMedCrossRefGoogle Scholar
  14. 14.
    Philipp W, Speicher L, Humpel C (2000) Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas. Invest Ophthalmol Vis Sci 41:2514–2522PubMedGoogle Scholar
  15. 15.
    Chang JH, Gabison EE, Kato T, Azar DT (2001) Corneal neovascularization. Curr Opin Ophthalmol 12:242–249PubMedCrossRefGoogle Scholar
  16. 16.
    Epstein RJ, Stulting RD, Hendricks RL, Harris DM (1987) Corneal neovascularization: pathogenesis and inhibition. Cornea 6:250–257PubMedCrossRefGoogle Scholar
  17. 17.
    Lee P, Wang CC, Adamis AP (1998) Ocular neovascularization: an epidemiologic review. Surv Ophthalmol 43:245–269PubMedCrossRefGoogle Scholar
  18. 18.
    Erdurmus M, Yagci R, Yilmaz B, Hepsen IF, Turkmen C, Aydin B, Karadag R (2007) Inhibitory effects of topical thymoquinone on corneal neovascularization. Cornea 26:715–719PubMedCrossRefGoogle Scholar
  19. 19.
    Jones IS, Meyer K (1950) Inhibition of vascularization of the rabbit cornea by local application of cotisone. Proc Soc Exp Biol Med 74:102–104PubMedCrossRefGoogle Scholar
  20. 20.
    Baratz KH, Hattenhauer MG (1999) Indiscriminate use of corticosteroid-containing eyedrops. Mayo Clin Proc 74:362–366PubMedCrossRefGoogle Scholar
  21. 21.
    Erdurmus M, Totan Y (2007) Subconjunctival bevacizumab for corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 245:1577–1579PubMedCrossRefGoogle Scholar
  22. 22.
    Bock F, König Y, Kruse F, Baier M, Cursiefen C (2008) Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 246:281–284PubMedCrossRefGoogle Scholar
  23. 23.
    Petsoglou C, Balaggan KS, Dart JK, Bunce C, Xing W, Ali RR, Tuft SJ (2013) Subconjunctival bevacizumab induces regression of corneal neovascularisation: a pilot randomised placebo-controlled double-masked trial. Br J Ophthalmol 97:28–32PubMedCrossRefGoogle Scholar
  24. 24.
    Dastjerdi MH, Al-Arfaj KM, Nallasamy N, Hamrah P, Jurkunas UV, Pineda R 2nd, Pavan-Langston D, Dana R (2009) Topical bevacizumab in the treatment of corneal neovascularization: results of a prospective, open-label, noncomparative study. Arch Ophthalmol 127:381–389PubMedCrossRefGoogle Scholar
  25. 25.
    Koenig Y, Bock F, Horn F, Kruse F, Straub K, Cursiefen C (2009) Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 247:1375–1382PubMedCrossRefGoogle Scholar
  26. 26.
    Joussen AM, Poulaki V, Mitsiades N, Stechschulte SU, Kirchhof B, Dartt DA, Fong GH, Rudge J (2003) VEGF-dependent conjunctivalization of the corneal surface. Invest Ophthalmol Vis Sci 44:117–123PubMedCrossRefGoogle Scholar
  27. 27.
    Bock F, Konig Y, Dietrich T, Zimmermann P, Baier M, Cursiefen C (2007) Inhibition of angiogenesis in the anterior chamber of the eye [in German]. Ophthalmologe 104:336–344PubMedCrossRefGoogle Scholar
  28. 28.
    Küchle M, Cursiefen C, Nguyen NX, Langenbucher A, Seitz B, Wenkel H, Martus P, Naumann GO (2002) Risk factors for corneal allograft rejection: intermediate results of a prospective normal-risk keratoplasty study. Graefes Arch Clin Exp Ophthalmol 240:580–584PubMedCrossRefGoogle Scholar
  29. 29.
    Maier P, Bohringer D, Reinhard T (2007) Clear graft survival and immune reactions following emergency keratoplasty. Graefes Arch Clin Exp Ophthalmol 245:351–359PubMedCrossRefGoogle Scholar
  30. 30.
    Maguire MG, Stark WJ, Gottsch JD, Stulting RD, Sugar A, Fink NE, Schwartz A (1994) Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative corneal transplantation studies research group. Ophthalmology 101:1536–1547PubMedGoogle Scholar
  31. 31.
    Shimazaki J, Den S, Omoto M, Satake Y, Shimmura S, Tsubota K (2011) Prospective, randomized study of the efficacy of systemic cyclosporine in high-risk corneal transplantation. Am J Ophthalmol 152:33–39.e1PubMedCrossRefGoogle Scholar
  32. 32.
    Gupta D, Illingworth C (2011) Treatments for corneal neovascularization: a review. Cornea 30:927–938PubMedCrossRefGoogle Scholar
  33. 33.
    Lipman RM, Epstein RJ, Hendricks RL (1992) Suppression of corneal neovascularization with cyclosporine. Arch Ophthalmol 110:405–407PubMedCrossRefGoogle Scholar
  34. 34.
    Cho ML, Cho CS, Min SY, Kim SH, Lee SS, Kim WU, Min DJ, Min JK, Youn J, Hwang SY, Park SH, Kim HY (2002) Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Arthritis Rheum 46:1202–1209PubMedCrossRefGoogle Scholar
  35. 35.
    Dastjerdi MH, Sadrai Z, Saban DR, Zhang Q, Dana R (2011) Corneal penetration of topical and subconjunctival bevacizumab. Invest Ophthalmol Vis Sci 52:8718–8723PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Yasin Yücel Bucak
    • 1
  • Mesut Erdurmus
    • 2
    Email author
  • Elçin Hakan Terzi
    • 3
  • Aysel Kükner
    • 3
  • Serdal Çelebi
    • 2
  1. 1.Ophthalmology ClinicIzzet Baysal State HospitalBoluTurkey
  2. 2.Department of OphthalmologyAbant Izzet Baysal University Medical SchoolBoluTurkey
  3. 3.Department of Histology and EmbryologyAbant Izzet Baysal University Medical SchoolBoluTurkey

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