Abstract
The aims of this study were to evaluate the effects of CM082 on the development of choroidal neovascularization (CNV) in a laser-induced CNV rat model and to determine the drug concentration in the ocular tissues. After the laser-induced CNV model was established in rats, CM082 was orally administered. The effects of CM082 on the CNV lesions were assessed using fundus fluorescein angiography (FFA), CNV histology, and retinal pigment epithelium- (RPE-) choroid-sclera eyecup analysis. The concentrations of CM082 in the plasma and eye tissues were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results of FFA, histology, and RPE-choroid-sclera eyecup analysis demonstrated that the CM082-treated (10 mg/kg/d or 30 mg/kg/d) rats exhibited significantly less neovascularization than did the control group. The total concentration of CM082 in the eyes (172.86 ± 57.11 ng/g) was similar to that in the plasma (196.87 ± 73.13 ng/ml). Within the eye, the concentrations of CM082 and its metabolites were highest in the retina-sclera. The orally administered CM082 thus effectively passed through the blood-retina barrier (BRB) to reach the retina in the Brown Norway rats. Therefore, at both 10 mg/kg/d and 30 mg/kg/d, CM082 was able to reduce CNV lesions in the laser-induced CNV rat model.
Highlights
Age-related macular degeneration (AMD) is one of the most common causes of irreversible central visual loss in people over 65 years of age in Europe and North America [1, 2]
Ten Brown Norway (BN) rats were photocoagulated in the oculus dexter (OD) to build the choroidal neovascularization (CNV) rat model
Histological examination was performed at day 21, while fundus fluorescein angiography (FFA) was conducted at days 14 and 21 to ensure that the CNV model was established successfully and to provide evidence that neovascularization was induced (Figures 1(a), 1(b), and 1(c))
Summary
Age-related macular degeneration (AMD) is one of the most common causes of irreversible central visual loss in people over 65 years of age in Europe and North America [1, 2]. The wet form accounts for only 10% of AMD cases, it is the main cause of visual loss in 60–80% of AMD patients [3, 4]. Anti-VEGF therapies that reduce the interaction of VEGF with its receptors, such as ranibizumab [13], aflibercept [14], and bevacizumab [15], are widely used to treat patients with CNV secondary to AMD and other pathological conditions. Reducing VEGF-A binding to VEGFRs, and especially VEGFR-2, is the main target of ranibizumab and bevacizumab [16]. These therapeutic drugs are relatively effective for treating AMD and related eye diseases, not all patients respond to them and many exhibit decreased drug susceptibility during treatment [17]. To avoid the intravitreal injection-related complications and relapse, it has been necessary to develop a less invasive treatment
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