Inhibitory effect of YC-1,3-(5 '-hydroxymethyl-2 '-furyl)-1-benzylindazole, on experimental choroidal neovascularization in rat

Department of Ophthalmology, Sungkyunkwan University, Sŏul, Seoul, South Korea
Ophthalmic Research (Impact Factor: 1.38). 01/2008; 40(1):35-40. DOI: 10.1159/000111157
Source: PubMed

ABSTRACT It was the aim of this study to evaluate the effects of YC-1, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, one of the hypoxia-inducible factor 1 (HIF-1) inhibitors, on laser-induced choroidal neovascularization (CNV) in rats.
Thirty female Brown Norway rats underwent laser photocoagulation to induce CNV. Twenty of them (treatment group) were treated with a single intravitreal injection of 5 microg YC-1, and the remaining 10 (control) were sham-treated with a single intravitreal injection of 2.5 mg/ml dimethyl sulfoxide 2 weeks after laser photocoagulation. The expression of HIF-1alpha and vascular endothelial growth factor (VEGF) in CNV was evaluated by immunofluorescence staining. Fluorescein angiography was performed 2 weeks before and 2 weeks after single intravitreal YC-1 (5 microg) and dimethyl sulfoxide (2.5 mg/ml) injection, grading fluorescein leakage from 0 to 3. The size of the CNV was measured on histologic sections.
Both HIF-1alpha and VEGF were expressed in CNV lesions in the control group 4 weeks after laser photocoagulation, whereas the expressions of HIF-1alpha and VEGF were not observed in the intravitreally YC-1-treated group. The mean fluorescein leakage score decreased from 2.56 +/- 0.49 to 0.79 +/- 0.71 in the intravitreally YC-1-injected group and from 2.62 +/- 0.49 to 1.58 +/- 0.60 in the control group. Sixty-eight (71.6%) out of 95 CNV lesions of intravitreally YC-1-treated eyes (71.4%) and 12 (21.8%) out of 55 lesions in DMSO-treated eyes showed a decreased fluorescein leakage score of 2 or more. The mean difference of fluorescein leakage scores between the intravitreally YC-1-treated group and the control group was significant (p = 0.004). The mean thickness of the CNV lesions in the intravitreally YC-1-treated group (27.30 +/- 6.47 microm) was smaller than that of the control group (64.36 +/- 8.26 microm, p < 0.001). There was no ocular inflammation, retina hemorrhage or systemic toxicity induced by YC-1 treatment.
These results suggest that YC-1 inhibits the HIF-1 expression after photocoagulation and suppresses the development of laser-induced CNV formation.

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    • "HIF-1α expression was detected in surgically excised human CNV membranes [82]–[83] and its level elevated in the eyes of laser induced CNV animal models (23, 18032914, 22915031) [23], [81]–[84]. While in pharmacologically or genetically HIF-1α-depleted mice, CNV was significantly suppressed with reduction of intraocular VEGF and/or ICAM-1 [23], [81]–[84]. Here, our results demonstrated that the HIF−1α activation induced by laser treatment was significantly suppressed by curcumin, which are compatible with previous results that curcumin or its derivate had the ability to down-regulated HIF−1α and VEGF expression in vascular endothelial cells and blocked angiogenesis in vitro [85]–[86]. Our data, at least in part, also suggest that the suppression of the expression of angiogenic and inflammatory molecules observed after laser injury is due to curcumin-induced inhibition of the NF-κB and HIF−1α pathway. "
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    • "As YC-1 is able to reduce RGC viability without inducing cell death, we think that YC-1 should be independent of RGC survival-related optic pathologies. Recently, Song et al. established that YC-1 can inhibit HIF-1 expression and laser-induced choroidal neovascularization in rats [49]. On the other hand, YC-1 was found to suppress pathological retinal neovascularization and enhance physiologic revascularization of the retinal vascular plexuses in a mouse with oxygen-induced retinopathy by impairing the ischemia-induced expression of HIF-1 and its downstream angiogenic molecules [50]. "
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