Abstract
Choroidal neovascularization (CNV) is a major cause of severe visual loss in patients with age-related macular degeneration (AMD). Recently, itraconazole has shown potent and dose-dependent inhibition of tumor-associated angiogenesis. We evaluated the anti-angiogenic effect of itraconazole in a rat model of laser-induced CNV. After laser photocoagulation in each eye to cause CNV, right eyes were administered intravitreal injections of itraconazole; left eyes received balanced salt solution (BSS) as controls. On day 14 after laser induction, fluorescein angiography (FA) was used to assess abnormal vascular leakage. Flattened retinal pigment epithelium (RPE)-choroid tissue complex was stained with Alexa Fluor 594-conjugated isolectin B4 to measure the CNV area and volume. Vascular endothelial growth factor receptor 2 (VEGFR2) mRNA and protein expression was determined 1, 4, 7, and 14 days after intravitreal injection by quantitative RT-PCR or Western blot. VEGF levels were analyzed by enzyme-linked immunosorbent assay (ELISA). Intravitreal itraconazole significantly reduced leakage from CNV as assessed by FA and CNV area and volume on flat mounts compared with intravitreal BSS (p = 0.002 for CNV leakage, p<0.001 for CNV area and volume). Quantitative RT-PCR showed significantly lower expression of VEGFR2 mRNA in the RPE-choroid complexes of itraconazole-injected eyes than those of BSS-injected eyes on days 7 and 14 (p = 0.003 and p = 0.006). Western blots indicated that VEGFR2 was downregulated after itraconazole treatment. ELISA showed a significant difference in VEGF level between itraconazole-injected and BSS-injected eyes on days 7 and 14 (p = 0.04 and p = 0.001). Our study demonstrated that intravitreal itraconazole significantly inhibited the development of laser-induced CNV in rats. Itraconazole had anti-angiogenic activity along with the reduction of VEGFR2 and VEGF levels. Itraconazole may prove beneficial for treating CNV as an alternative or adjunct to other therapies.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness in older people in industrialized countries [1]
To assess the inhibitory effect of itraconazole on choroidal neovascularization (CNV) formation, fluorescein angiography (FA) and isolectin B4 staining of retinal pigment epithelium (RPE)-choroid complex flat mounts were conducted on day 14 after inducing CNV
FA showed that intravitreal itraconazole significantly reduced fluorescein leakage from CNV compared with intravitreal balanced salt solution (BSS) (Fig 1A)
Summary
Age-related macular degeneration (AMD) is the leading cause of blindness in older people in industrialized countries [1]. The CNV pathogenesis is not clearly understood, pathological angiogenesis mediated by growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor, is important in CNV development. These factors induce activation of signaling pathways after binding receptors on endothelial cells. Several key signaling mediators including phospholipase C, phosphatidylinositol-3 kinase, and protein kinase C deliver angiogenic signals to stimulate endothelial cell proliferation, migration, and survival
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