Intravitreal injection of specific receptor tyrosine kinase inhibitor PTK787/ZK222 584 improves ischemia-induced retinopathy in mice

Background: Retinal neovascularisation occurs under the influence of angiogenic factors that are induced by hypoxia, like vascular endothelial growth factor ( VEGF), which is one of the major mediators. PTK/ZK inhibits VEGF signal transduction by blocking the tyrosine kinase of all three VEGF receptors. PTK/ZK is currently being evaluated in clinical trials for angioinhibitory therapy in tumour patients. To avoid potential systemic side effects, local application would be desirable for the treatment of ischemic retinopathies in humans. We therefore investigated the effect of intravitreally applied PTK/ ZK in a mouse model for ischemia-induced retinopathy. Methods: C57BL/6J mice were placed in 75% oxygen on postnatal day 7. On day 12, they were treated with an intravitreal injection of PTK/ ZK ( 5 mu M or 40 mu M) in one eye and buffer solution in the fellow eye. Afterwards, the animals were kept in room air until intracardial perfusion with fluorescein-dextran on day 17. Retinal whole mounts were prepared and ischemic retinopathy was evaluated using a standardised retinopathy score. Results: A single intravitreal injection of 40 mu M PTK/ZK reduced angioproliferative changes compared to the control eye of each animal (n = 37). The difference in retinopathy scores was highly significant (P = 0.002, Wilcoxon signed-rank test). Injection of 5 mu M PTK/ZK did not show a significant antiangiogenic effect. Conclusions: Tyrosine kinase inhibitors are promising substances not only in cancer therapy, but also in the treatment of ischemic retinopathies that are mediated by VEGF. We showed that in a mouse model for ischemia-induced retinopathy a single intravitreal injection of 40 mu M PTK/ ZK is capable of significantly reducing angioproliferative retinopathy. The local application of PTK/ ZK could be a new way to treat ischemic ocular diseases such as diabetic retinopathy in humans.