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Local Injection of Receptor Tyrosine Kinase Inhibitor MAE 87 Inhibits Retinal Neovascularization in Mice
1Unsöld A. S., 1Junker B., 2Mazitschek R., 1Hansen L. L., 2Giannis A., 1Agostini H.,
1Albert-Ludwigs-Universität, Augenklinik (Freiburg)
2Universität Leipzig, Institut für Organische Chemie (Leipzig)
Purpose: Retinal neovascularization (RNV) occurs under the influence of angiogenic factors of which VEGF (vascular endothelial growth factor) is one of the major mediators. VEGF signaling is enhanced by IGF-1 (insuline like growth factor) which is increased in diabetic retinopathy. MAE 87 is an oxoindolinone that inhibits VEGF signal transduction in vitro by blocking the tyrosine kinase of VEGF receptor 2 and 3 as well as the receptor of IGF-1 to some extent. The aim of our investigation was to determine the effect of MAE 87 on oxygen-induced proliferative retinopathy (RP) in mice.
Methods: C57BL/6J mice were placed in a 76% oxygen environment 7 days after birth (P7). On P12 they were removed from the oxygen incubator and treated with an intravitreal injection (2µl) of MAE 87 (40µM) in one eye and buffer solution in the fellow eye. The animals were kept at room air and sacrificed by intracardial perfusion with fluorescein-dextran on P17. Retinal whole mounts were prepared and ischemic RP was evaluated using a RP score adapted from Higgins et al. (1999).
Results: A single intravitreal injection of MAE 87 reduced the angioproliferative changes compared with the control eye of each animal. The difference in the RP scores was highly significant (p=0.005) using a paired t-test.
Conclusions: Tyrosine kinase inhibitors are promising substances in the treatment of intraocular neovascularization and inhibition of tumor angiogenesis. In a mouse model of RNV, local treatment with MAE 87 reduced RP markedly. In diabetic RP rapid normalization of blood glucose with insulin is accompanied by an initial increase in RNV that goes along with rising IGF-1 levels. Since the MAE 87-specificity includes the IGF-1 receptor, the drug might prove especially useful for the treatment of diabetic RP.