Inhibition of corneal neovascularization by topical application of nintedanib in rabbit models
Author:
Corresponding Author:

Wen-Zhen Yu. Department of Ophthalmology, Peking University People’s Hospital; Eye Diseases and Optometry Institute; Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases; College of Optometry, Peking University Health Science Center, Xizhimen Nandajie 11, Xicheng District, Beijing 100044, China. wenzhen_yu@sina.com

Fund Project:

Supported by the Natural Science Foundation of Tianjin City (No.2150000045).

  • Article
  • | |
  • Metrics
  • |
  • Reference [26]
  • |
  • Related [20]
  • | | |
  • Comments
    Abstract:

    AIM: To evaluate the potential efficacy and mechanisms of nintedanib in corneal neovascularization (NV) in rabbit models. METHODS: Corneal NV was induced using 1 mol/L NaOH. Rabbits (n=21) were randomized to 3 groups: Group 1 were treated with 0.9% NaCl, Group 2 with Avastin (5 mg/mL), and Group 3 with nintedanib (1 mg/mL). All treatments started 1d after alkaline burns and were topically performed 3 times a day for 2wk. Photographs were taken on a slit lamp microscope on day 7 and 14. The NV area, the length of the vascularization and angiogenesis index (AI) were used to evaluate the corneal NV. On day 14, the immunohistochemical (IHC) studies of the cornea were examined. Western blot was performed to test the expression levels of vascular endothelial growth factor (VEGF), Akt, p-Akt, P38, p-P38, MMP-2 and MMP-9. RESULTS: The corneal NV area, vessel length and AI in Group 3 were significantly lower than Group 2, with both being lower than Group 1. IHC staining showed that VEGF was significantly overexpressed in the epithelium and stroma of cornea following alkaline burns. In contrast, the level of VEGF was significantly suppressed in both Group 2 and Group 3. Western blot results further confirmed that, compared with Group 1, Group 3 had significantly reduced expressions of VEGF, Akt, p-Akt, p-P38, MMP-2, and MMP-9 in corneal tissues. Trends of lower levels of MMP-2, AKT, and p-AKT in Group 3 than Group 2 were identified. CONCLUSION: Nintedanib and Avastin can effectively inhibit corneal NV, with P38 MAPK and AKT signaling pathways being possibly involved. Nintedanib seems more effective than Avastin and has the potential to be a novel therapy for preventing corneal NV.

    Reference
    1 Sharif Z, Sharif W. Corneal neovascularization: updates on pathophysiology, investigations & management. Rom J Ophthalmol 2019;63(1):15-22.
    2 Liu XY, Wang SR, Wang XZ, Liang JM, Zhang Y. Recent drug therapies for corneal neovascularization. Chem Biol Drug Des 2017;90(5): 653-664.
    3 Lopez ES, Ortiz GA, Potilinski C, Croxatto JO, Gallo JE. Corneal neovascularization: a combined approach of bevacizumab and suramin showed increased antiangiogenic effect through downregulation of BFGF and P2X2. Curr Eye Res 2018;43(4):466-473.
    4 Gonzalez L, Loza RJ, Han KY, Sunoqrot S, Cunningham C, Purta P, Drake J, Jain S, Hong S, Chang JH. Nanotechnology in corneal neovascularization therapy—a review. J Ocul Pharmacol Ther 2013;29(2):124-134.
    5 Waisbourd M, Levinger E, Varssano D, Moisseiev E, Zayit-Soudri S, Barak A, Loewenstein A, Barequet I. High-dose topical bevacizumab for corneal neovascularization. Pharmacology 2013;92(5-6):310-314.
    6 Hosseini H, Nejabat M, Mehryar M, Yazdchi T, Sedaghat A, Noori F. Bevacizumab inhibits corneal neovascularization in an alkali burn induced model of corneal angiogenesis. Clin Exp Ophthalmol 2007;35(8):745-748.
    7 You IC, Kang IS, Lee SH, Yoon KC. Therapeutic effect of subconjunctival injection of bevacizumab in the treatment of corneal neovascularization. Acta Ophthalmol 2009;87(6):653-658.
    8 Gong Y, Wu GH, Zhang LY, Zhang Z, Liao YH, Liu XT. Effect of nintedanib thermo-sensitive hydrogel on neovascularization in alkali burn rat model. Int J Ophthalmol 2020;13(6):879-885.
    9 Tamargo RJ, Bok RA, Brem H. Angiogenesis inhibition by minocycline. Cancer Res 1991;51(2):672-675.
    10 Barry Z, Park B, Corson TW. Pharmacological potential of small molecules for treating corneal neovascularization. Molecules 2020;25(15):E3468.
    11 Bachmann B, Taylor RS, Cursiefen C. Corneal neovascularization as a risk factor for graft failure and rejection after keratoplasty: an evidence-based meta-analysis. Ophthalmology 2010;117(7):1300-1305.e7.
    12 Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2:structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 2007;19(10):2003-2012.
    13 Sahan B, Ciftci F, Eyuboglu S, Yaba A, Yilmaz B, Yalvac BI. Comparison of the effects of dovitinib and bevacizumab on reducing neovascularization in an experimental rat corneal neovascularization model. Cornea 2019;38(9):1161-1168.
    14 Papathanassiou M, Theodossiadis PG, Liarakos VS, Rouvas A, Giamarellos-Bourboulis EJ, Vergados IA. Inhibition of corneal neovascularization by subconjunctival bevacizumab in an animal model. Am J Ophthalmol 2008;145(3):424-431.
    15 Bock F, Onderka J, Dietrich T, Bachmann B, Kruse FE, Paschke M, Zahn G, Cursiefen C. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci 2007;48(6):2545-2552.
    16 Yoeruek E, Ziemssen F, Henke-Fahle S, Tatar O, Tura A, Grisanti S, Bartz-Schmidt KU, Szurman P, Tübingen Bevacizumab Study Group. Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn. Acta Ophthalmol 2008;86(3):322-328.
    17 Koenig Y, Bock F, Horn F, Kruse F, Straub K, Cursiefen C. Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corne????????????????????n. Graefes Arch Clin Exp Ophthalmol 2009;247(10):1375-1382.
    18 Roshandel D, Eslani M, Baradaran-Rafii A, Cheung AY, Kurji K, Jabbehdari S, Maiz A, Jalali S, Djalilian AR, Holland EJ. Current and emerging therapies for corneal neovascularization. Ocul Surf 2018;16(4):398-414.
    19 Pérez-Santonja JJ, Campos-Mollo E, Lledó-Riquelme M, Javaloy J, Alió JL. Inhibition of corneal neovascularization by topical bevacizumab (anti-VEGF) and Sunitinib (anti-VEGF and anti-PDGF) in an animal model. Am J Ophthalmol 2010;150(4):519-528.e1.
    20 Dursun A, Arici MK, Dursun F, Ozec AV, Toker MI, Erdogan H, Topalkara A. Comparison of the effects of bevacizumab and ranibizumab injection on corneal angiogenesis in an alkali burn induced model. Int J Ophthalmol 2012;5(4):448-451.
    21 Jo N, Mailhos C, Ju MH, Cheung E, Bradley J, Nishijima K, Robinson GS, Adamis AP, Shima DT. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 2006;168(6):2036-2053.
    22 Sasore T, Reynolds AL, Kennedy BN. Targeting the PI3K/Akt/mTOR pathway in ocular neovascularization. Adv Exp Med Biol 2014;801:805-811.
    23 Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 2008;75(2):346-359.
    24 Yu H, Sun L, Cui J, Li Y, Yan Y, Wei X, Wang C, Song F, Jiang W, Liu Y, Ge H, Qian H, Li X, Tang X, Liu P. Three kinds of corneal host cells contribute differently to corneal neovascularization. EBioMedicine 2019;44:542-553.
    25 Jin Y, Chai LJ, Hong J. Early expression of tumor necrosis factor α and nuclear factor kappa B after Descemet stripping endothelial keratoplasty in rabbits. Cornea 2012;31(8):913-919.
    26 Lennikov A, Mirabelli P, Mukwaya A, Schaupper M, Thangavelu M, Lachota M, Ali Z, Jensen L, Lagali N. Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis. Angiogenesis
    Cited by
    Comments
    Comments
    分享到微博
    Submit
Get Citation

Juan Chen, Xue Ding, Wei Du,/et al.Inhibition of corneal neovascularization by topical application of nintedanib in rabbit models. Int J Ophthalmol, 2021,14(11):1666-1673

Copy
Share
Article Metrics
  • Abstract:950
  • PDF: 689
  • HTML: 0
  • Cited by: 0
Publication History
  • Received:November 15,2020
  • Revised:May 10,2021
  • Online: October 27,2021