370 590

Cited 0 times in

Inhibitory effect of itraconazole on laser-induced choroidal neovascularization in rats

Other Titles
 쥐에서 레이저로 유도된 맥락막신생혈관에 대한 이트라코나졸의 억제 효과 
 Dept. of Ophthalmology (안과학교실) 
Issue Date
Age-related macular degeneration (AMD) is the leading cause of blindness in older people in developed countries. Severe vision loss in patients with AMD is commonly due to choroidal neovascularization (CNV). Current CNV treatments, such as laser photocoagulation, photodynamic therapy, and intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs, have limited efficacy in improving vision. Patients often require repeated treatment because of recurrence. Multiple intraocular injections are associated with serious complications and high treatment costs.

Itraconazole, a relatively safe antifungal drug, has anti-angiogenic effects. In recent studies, itraconazole showed potent and selective inhibition of tumor-associated angiogenesis in murine models and in vitro assays using human endothelial cells. Itraconazole dose-dependently inhibited angiogenesis, suggesting it may be useful in treating pathological angiogenesis. The aim of this study was to evaluate the anti-angiogenic effect of itraconazole on laser-induced CNV in rats.

Six laser burns were induced in the peripapillary area of each eye of male, adult Brown Norway rats (200-250 g) to cause CNV. Right eyes were administered intravitreal injections of 1 μg/10 μl itraconazole; left eyes received 10 μl 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 488-conjugated isolectin B4 to measure the CNV areas with an image analysis program. VEGF receptor 2 (VEGFR2) mRNA and protein expression and phosphorylation of Akt and ERK were determined by quantitative RT-PCR or Western blot. The VEGF concentration in the retina was analyzed by enzyme-linked immunosorbent assay (ELISA).

Intravitreal itraconazole significantly reduced leakage from CNV as assessed by FA and CNV area on flat mounts of the RPE-choroid complex when compared with intravitreal BSS on day 14 after laser induction (P = 0.002 for CNV leakage, P < 0.001 for CNV area). Quantitative RT-PCR showed significantly lower expression of VEGFR2 mRNA in RPE-choroid complexes from itraconazole-injected eyes than from BSS-injected eyes (P < 0.001). Western blots indicated that VEGFR2 was downregulated after 14 days of itraconazole treatment. ELISA assay showed a significant difference in VEGF concentration between itraconazole- and BSS-injected eyes (801.7 ± 187.5 vs. 988.0 ± 232.8 pg/mg total protein; P = 0.043). However, phosphorylation of Akt and ERK showed no significant differences between groups at day 14 after laser induction (P = 0.258 for p-Akt, P = 0.730 for p-ERK).

In conclusion, this study demonstrated that intravitreal itraconazole significantly inhibited the development of laser-induced CNV in rats. Itraconazole had anti-angiogenic activity by reducing VEGFR2 expression and inhibiting VEGF activity. Itraconazole may prove beneficial for treating CNV as an alternative or adjunct to other therapies.
Files in This Item:
T013839.pdf Download
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 3. Dissertation
Yonsei Authors
Bae, Jeong Hun(배정훈)
사서에게 알리기


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.