The Impact of Subconjuctivally Injected EGF and VEGF Inhibitors on Experimental Corneal Neovascularization in Rat Model

Sener, Ender; Yuksel, Nusen; Yıldız, Demir Kürşat; Yılmaz, Bülent; Özdemir, Özdemir; Çağlar, Yusuf; Degirmenci, Esra

doi:10.3109/02713683.2011.601840

Cited by 41 publications

(37 citation statements)

References 46 publications

(48 reference statements)

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“…Anti-VEGF treatment did not appear to suppress myeloid cell recruitment at day 2 and 7 in our model in contrast to other rat models of corneal injury, where inflammatory cells were significantly suppressed by subconjunctival administration of bevacizumab (Oh et al, 2009;Sener et al, 2011) but not ranibizumab (Sener et al, 2011). Conflicting results may be due to different models, species-dependent effects (we used rat-specific anti-VEGF), quantification techniques, and drug delivery methods.…”

Section: Discussioncontrasting

confidence: 48%

“…The model, designed for longitudinal in vivo examination, induces vessels in a well-defined region of the cornea between the limbus and the suture, limited to about one-tenth of the cornea's total surface area. In other animal models with several central sutures (Bock et al 2007;Cursiefen et al, 2004;Hos et al, 2011) or a large-area alkali burn (Dratviman-Storobinsky et al, 2009;Gong and Koh, 2010;Hoffart et al, 2010;Sener et al, 2011) a large region of the cornea can become vascularized, which allows for greater sensitivity in detecting significant reductions in invasion area, but a less predictable and controlled pattern of vascularization.…”

Section: Discussionmentioning

confidence: 99%

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Early effects of dexamethasone and anti-VEGF therapy in an inflammatory corneal neovascularization model

Mirabelli

Peebo

Xeroudaki

et al. 2014

Experimental Eye Research

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Inflammatory angiogenesis is the pathogenic mechanism of various sight-threatening eye diseases, among them corneal neovascularization. Current treatment options include steroids which have undesirable side effects, or anti-VEGF which has only limited efficacy. In an inflammatory environment, however, angiogenesis can be stimulated by numerous factors not directly targeted by anti-VEGF therapy. The aim of this study was to induce corneal inflammation leading to angiogenesis, and investigate the early, differential effects of steroid and anti-VEGF therapy at the cellular, tissue, and gene expression levels. Fifty-two Wistar rats received a single intrastromal corneal suture to induce a controlled inflammatory angiogenic response. Rats were subsequently treated with dexamethasone, rat specific anti-VEGF, or goat IgG (control), topically 4 times daily for 7 days. In vivo confocal microscopy of the cornea was performed longitudinally from 5 h up to 7 d to investigate morphology at the cellular and tissue-level. In vivo photographic vessel analysis and immunohistochemistry were also performed. RT-PCR for VEGF-A, FGF-2, IL-6, TNF-alpha, CXCL2, CCL2, CCL3 and DLL4 was performed at 24 h, and for VEGF-A, IL-6, TNF-alpha, FGF-2, CXCL2, CCL2, and CCL3 at 7 days. Early infiltration of CD11b + myeloid cells into the cornea at 5 h post-suture was delayed by both treatments relative to controls; however neither treatment was able to suppress accumulation of myeloid cells at day 2 or 7. Limbal vessel dilation was inhibited at 5 h by both treatments, but only dexamethasone showed sustained effect until day 2. Early macrophage recruitment was also suppressed by dexamethasone (but not by anti-VEGF) until day 2. Dexamethasone furthermore suppressed corneal neovascularization at day 7 by over 90%, whereas suppression by anti-VEGF was 14%. Despite differential suppression of vessel dilation, macrophage recruitment, and vascular invasion, anti-VEGF and dexamethasone both down-regulated VEGF-A and IL-6 expression at 24 h with sustained effect to 7 d. They also both down regulated FGF-2 and TNF-alpha at 24 h and CCL2 at 7 d. In conclusion, anti-angiogenic treatments influence early, pre-angiogenic tissue activity such as limbal vessel dilation, inflammatory cell infiltration of the stroma, and macrophage recruitment. Importantly, the differential effects of steroids and anti-VEGF treatment in suppressing neovascular growth could not be attributed to differential inhibition of several major angiogenic and inflammatory factors in the early pre-sprouting phase, including IL-6, VEGF-A, FGF-2, TNF-alpha, CCL2, CCL3, CXCL2, or DLL4.

Funding Agencies|Crown Princess Margaretas Foundation; County Council of Ostergotland; Swedish Research Council [2012-2472]

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Early effects of dexamethasone and anti-VEGF therapy in an inflammatory corneal neovascularization model

Mirabelli

Peebo

Xeroudaki

et al. 2014

Experimental Eye Research

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Funding Agencies|Crown Princess Margaretas Foundation; County Council of Ostergotland; Swedish Research Council [2012-2472]

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“…ranibizumab. It has been reported that bevacizumab, ranibizumab, pegaptanib, and trastuzumab all have the ability to inhibit corneal neovascularization, and that bevacizumab is the most effective treatment in an experimental rat model (18) . Various experimental and clinical studies have reported that bevacizumab inhibits corneal neovascularization when used at different doses both topically and subconjunctivally (11)(12)(13) .…”

Section: Discussionmentioning

confidence: 99%

Comparison of the effects of subconjunctival and topical anti-VEGF therapy (bevacizumab) on experimental corneal neovascularization

Özdemir¹,

Altıntaş²,

Altıntaş³

et al. 2014

Arquivos Brasileiros De Oftalmologia

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Purpose: To compare the effects of bevacizumab applied either subconjunctivally or topically, in a rat model of corneal neovascularization induced by alkali burn. Methods: The right corneas of 24 Wistar-Albino rats were cauterized with silver nitrate sticks. The rats were divided randomly and equally into three groups: no treatment control (n=8), subconjunctival bevacizumab treatment (n=8), and topical bevacizumab treatment (n=8). Immediately following cauterization, the subconjunctival group was treated with a 0.05 ml (1.25 mg) bevacizumab subconjunctival injection. The topical group was treated with 10 mg/ml bevacizumab twice daily, and the control group received subconjunctival saline injections twice daily. The burn stimulus and neovascularization scores were evaluated using a technique previously described by Mahoney and Waterbury. Digital photographs were obtained before the eyes were enucleated and corneal sections were then analyzed by histopathology. Results: The mean burn stimulus score was 1.86 ± 0.6 and there was no statistical difference between the groups (p=0.730). The mean neovascularization scores in the subconjunctival and topical bevacizumab groups were statistically lower than the control group (p<0.05). The mean percentage area of corneal neovascularization was 82.5 ± 22.1 in the control group, 42.7 ± 15.0 in the subconjunctival group, and 55.8 ± 18.2 in the topical group. The differences between the control and treatment groups were statistically significant (p<0.05). Histopathology showed that the treatment groups presented less neovascularization, inflammation, and fibroblast activity than the control group (p<0.05). Conclusions: This study demonstrates that both subconjunctival and topical administrations of bevacizumab inhibit corneal neovascularization and decrease inflammation and fibroblast activity in a rat model of corneal neovascularization induced by alkali burn.

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“…Similarly, a recent study conducted by Sener et al investigated the inhibitory effects of subconjunctival application of various VEGF antibodies, including bevacizumab, ranibizumab, and pegaptanib, as well as the Human Epidermal Growth Factor Receptor (HER)-2 antibody, trastuzumab, in a rat model of experimental corneal NV. 33 These VEGF antibodies were all found to be effective in reducing corneal NV. However, bevacizumab was found to be the most effective of the group.…”

Section: Anti-vegf Treatmentsmentioning

confidence: 99%

Nanotechnology in Corneal Neovascularization Therapy—A Review

Gonzalez

Loza

Han

et al. 2013

Journal of Ocular Pharmacology and Therapeutics

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Nanotechnology is an up-and-coming branch of science that studies and designs materials with at least one dimension sized from 1-100 nm. These nanomaterials have unique functions at the cellular, atomic, and molecular levels.1 The term ''nanotechnology'' was first coined in 1974. 2 Since then, it has evolved dramatically and now consists of distinct and independent scientific fields. Nanotechnology is a highly studied topic of interest, as nanoparticles can be applied to various fields ranging from medicine and pharmacology, to chemistry and agriculture, to environmental science and consumer goods. 3 The rapidly evolving field of nanomedicine incorporates nanotechnology with medical applications, seeking to give rise to new diagnostic means, treatments, and tools. Over the past two decades, numerous studies that underscore the successful fusion of nanotechnology with novel medical applications have emerged. This has given rise to promising new therapies for a variety of diseases, especially cancer. It is becoming abundantly clear that nanotechnology has found a place in the medical field by providing new and more efficient ways to deliver treatment. Ophthalmology can also stand to benefit significantly from the advances in nanotechnology research. As it relates to the eye, research in the nanomedicine field has been particularly focused on developing various treatments to prevent and/or reduce corneal neovascularization among other ophthalmologic disorders. This review article aims to provide an overview of corneal neovascularization, currently available treatments, and where nanotechnology comes into play.

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The Impact of Subconjuctivally Injected EGF and VEGF Inhibitors on Experimental Corneal Neovascularization in Rat Model

Abstract: Bevacizumab, ranibizumab, pegaptanib, and trastuzumab were found effective for the inhibition of corneal NV. In our study we detected that the most effective agent was bevacizumab.

Cited by 41 publications

References 46 publications

Early effects of dexamethasone and anti-VEGF therapy in an inflammatory corneal neovascularization model

Early effects of dexamethasone and anti-VEGF therapy in an inflammatory corneal neovascularization model

Comparison of the effects of subconjunctival and topical anti-VEGF therapy (bevacizumab) on experimental corneal neovascularization

Nanotechnology in Corneal Neovascularization Therapy—A Review

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