Dataset Information

Therapeutic Effects of a Novel Phenylphthalimide Analog for Corneal Neovascularization and Retinal Vascular Leakage.

ABSTRACT:

Purpose

Neovascularization (NV) and retinal vascular leakage are major causes of impaired vision in ocular diseases. The purpose of this study was to identify novel phenylphthalimide analogs with therapeutic effects on NV and vascular leakage and to explore the mechanism of action.

Methods

Antiangiogenic activities of novel phenylphthalimide analogs were assessed in vitro by using VEGF ELISA and endothelial cell proliferation assay. Their efficacies on retinal vascular leakage were evaluated using rat models of oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced diabetes. The in vivo antiangiogenic activity was evaluated using topical administration in the alkali burn-induced corneal NV model. The expression of VEGF and intercellular adhesion molecule-1 (ICAM-1) were measured using ELISA.

Results

Thalidomide and three novel analogs all showed inhibitory effects on endothelial cell proliferation and VEGF expression in vitro. Through intravitreal injection, all of the compounds reduced retinal vascular leakage in the OIR and STZ-induced diabetic models. Among these compounds, (2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3-dione (DAID) displayed the most potent efficacy and reduced retinal vascular leakage in a dose-dependent manner in both the OIR and STZ-diabetes models. Topical administration of DAID also inhibited alkali burn-induced corneal NV. Furthermore, DAID attenuated the overexpression of VEGF and ICAM-1 in the retina of the OIR model. Intravitreal injection of DAID did not result in any detectable side effects, as shown by electroretinogram and retinal histological analysis.

Conclusions

DAID is a novel phenylphthalimide analog with potent effects on NV and retinal vascular leakage through downregulation of VEGF and inflammatory factors and has therapeutic potential.

SUBMITTER: Wang B

PROVIDER: S-EPMC6054429 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Therapeutic Effects of a Novel Phenylphthalimide Analog for Corneal Neovascularization and Retinal Vascular Leakage.

Wang Bing B Li Pui-Kai PK Ma Jian-Xing JX Chen Danyang D

Investigative ophthalmology & visual science 20180701 8

<h4>Purpose</h4>Neovascularization (NV) and retinal vascular leakage are major causes of impaired vision in ocular diseases. The purpose of this study was to identify novel phenylphthalimide analogs with therapeutic effects on NV and vascular leakage and to explore the mechanism of action.<h4>Methods</h4>Antiangiogenic activities of novel phenylphthalimide analogs were assessed in vitro by using VEGF ELISA and endothelial cell proliferation assay. Their efficacies on retinal vascular leakage wer ...[more]

PMID: 30029250

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Project description:The purpose of this study was to characterize and develop a primate model of chronic retinal neovascularization and vascular leakage that can be employed to assess efficacy of experimental therapeutics targeting retinal ischemic and neovascular diseases. African green monkeys received bilateral intravitreal (IVT) injection of DL-alpha-aminoadipic acid (DLAAA; 5 mg) following ophthalmic examination, color fundus photography, fluorescein angiography (FA) and optical coherence tomography (OCT). Imaging was repeated to evaluate progression and subsequent stabilization of retinal vascular pathology elicited by DLAAA. Aflibercept (Eylea) was administered IVT (1.4 mg) to assess effects on vascular leakage. Ocular tissue was collected for histopathology and glial fibrillary acidic protein (GFAP), von Willebrand Factor (vWF), CD105/endoglin, VEGF and CD68 immunohistochemistry to study retinal degeneration and vascular remodeling. IVT DLAAA administration resulted in telangiectatic vessel formation as early as two-weeks post-injection, followed by retinal vascular leakage and inner retinal edema. Neovascular lesion progression was evident up to 8-10 weeks post-injection before stabilizing into a vascular leakage state that persisted beyond 90 weeks. Histopathology and immunostaining revealed retinal degeneration and neovascularization, increased expression of vWF, CD105/endoglin, VEGF and CD68 immunoreactivities in addition to Müller cell loss. Aflibercept significantly attenuated vascular leakage for 2-4 weeks before progressive return of leakage from weeks 4-8. Lesions remained responsive to anti-VEGF administration at 90 weeks after DLAAA injection. Findings support application of the primate DLAAA-induced retinal vascular leakage model for efficacy evaluations of candidate therapeutics and sustained release strategies targeting exudative AMD, diabetic retinopathy, macular telangiectasia and other retinal ischemic and neovascular diseases. Findings confirm relevance of the DLAAA primate phenotype to understanding shared retinal vascular disease mechanisms and macular susceptibility to vascular and metabolic insults.

Project description:PurposeTo determine thrombospondin-2 (TSP2) expression and its impact on postnatal retinal vascular development and retinal neovascularization.MethodsThe TSP2-deficient (TSP2(-/-)) mice and a line of TSP2 reporter mice were used to assess the expression of TSP2 during postnatal retinal vascular development and neovascularization. The postnatal retinal vascularization was evaluated using immunostaining of wholemount retinas prepared at different postnatal days by collagen IV staining and/or TSP2 promoter driven green fluorescent protein (GFP) expression. The organization of astrocytes was evaluated by glial fibrillary acidic protein (GFAP) staining. Retinal vascular densities were determined using trypsin digestion preparation of wholemount retinas at 3- and 6-weeks of age. Retinal neovascularization was assessed during the oxygen-induced ischemic retinopathy (OIR). Choroidal neovascularization (CNV) was assessed using laser-induced CNV.ResultsUsing the TSP2-GFP reporter mice, we observed significant expression of TSP2 mRNA in retinas of postnatal day 5 (P5) mice, which increased by P7 and remained high up to P42. Similar results were observed in retinal wholemount preparations, and western blotting for GFP with the highest level of GFP was observed at P21. In contrast to high level of mRNA at P42, the GFP fluorescence or protein level was dramatically downregulated. The primary retinal vasculature developed at a faster rate in TSP2(-/-) mice compared with TSP2(+/+) mice up to P5. However, the developing retinal vasculature in TSP2(+/+) mice caught up with that of TSP2(-/-) mice after P7. No significant differences in retinal vascular density were observed at 3- or 6-weeks of age. TSP2(-/-) mice also exhibited a similar sensitivity to the hyperoxia-mediated vessel obliteration and similar level of neovascularization during OIR as TSP2(+/+) mice. Lack of TSP2 expression minimally affected laser-induced CNV compared with TSP2(+/+) mice.ConclusionsLack of TSP2 expression was associated with enhanced retinal vascularization during early postnatal days but not at late postnatal times, and minimally affected retinal and CNV. However, the utility of TSP2 as a potential therapeutic target for inhibition of ocular neovascularization awaits further investigation.

Dataset Information

Therapeutic Effects of a Novel Phenylphthalimide Analog for Corneal Neovascularization and Retinal Vascular Leakage.

Purpose

Methods

Results

Conclusions

Publications

Therapeutic Effects of a Novel Phenylphthalimide Analog for Corneal Neovascularization and Retinal Vascular Leakage.

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