Department of Ophthalmology and Eye Hospital, University of Leipzig, D-04103 Leipzig, Germany.
Eur J Pharmacol. 2011 Sep;666(1-3):12-8. doi: 10.1016/j.ejphar.2011.05.016. Epub 2011 May 20.
Neovascularization in the eye is a major cause of irreversible vision loss. The present study was undertaken to determine mechanisms through which pazopanib, a drug that targets multiple receptor tyrosine kinases such as VEGF receptors, inhibits angiogenesis and experimental choroidal neovascularization (CNV). Pazopanib inhibited VEGF expression by retinal pigment epithelium (RPE) cells and choroidal endothelial cells (CEC), decreased VEGF-induced cellular migration in a dose-dependent manner and suppressed extracellular signal-regulated kinase (ERK)-1/-2 phosphorylation. To assess the impact of pazopanib in vivo, CNV was induced in rats by rupturing the Bruch's membrane by laser coagulation. These experiments demonstrated that twice-daily topical eye drop treatment significantly (P<0.001) decreased leakage from photocoagulated lesions by 89.5%. Furthermore, the thickness of the developed CNV lesions was significantly inhibited by 71.7% (P<0.001) in pazopanib-treated eyes, and immunoreactivity of VEGF was lower than in control eyes. Our data suggest that pazopanib is a promising inhibitor of angiogenesis leading to an effective inhibition of CNV development in vivo. This activity can be largely ascribed to the down-regulation of VEGF release in the retina as well as to impaired VEGF-induced signaling and chemotaxis. Using a convenient topical dosing regimen, pazopanib may prove useful for treating a variety of ocular neovascular diseases such as neovascular age-related macular degeneration.
眼部新生血管是导致不可逆视力丧失的主要原因。本研究旨在确定帕唑帕尼（一种针对多种受体酪氨酸激酶，如 VEGF 受体的药物）抑制血管生成和实验性脉络膜新生血管（CNV）的机制。帕唑帕尼抑制视网膜色素上皮（RPE）细胞和脉络膜内皮细胞（CEC）中 VEGF 的表达，以剂量依赖的方式降低 VEGF 诱导的细胞迁移，并抑制细胞外信号调节激酶（ERK）-1/-2 磷酸化。为了评估帕唑帕尼在体内的影响，通过激光凝固破坏 Bruch 膜在大鼠中诱导 CNV。这些实验表明，每日两次局部滴眼治疗显著（P<0.001）降低了光凝损伤的渗漏 89.5%。此外，帕唑帕尼治疗组的 CNV 病变厚度显著抑制了 71.7%（P<0.001），VEGF 的免疫反应性低于对照组。我们的数据表明，帕唑帕尼是一种有前途的血管生成抑制剂，可有效抑制体内 CNV 的发展。这种活性在很大程度上归因于视网膜中 VEGF 释放的下调，以及 VEGF 诱导的信号转导和趋化作用受损。使用方便的局部给药方案，帕唑帕尼可能对治疗各种眼部新生血管疾病（如新生血管性年龄相关性黄斑变性）有用。
