Local injection of receptor tyrosine kinase inhibitor MAE 87reduces retinal neovascularization in mice

[摘要] Purpose: Retinal neovascularization occurs under the influence ofangiogenic factors like vascular endothelial growth factor (VEGF). VEGFsignaling is enhanced by insulin-like growth factor-1 (IGF-1). In vitro,the oxoindolinone MAE 87 inhibits angiogenic signal transduction byblocking tyrosine kinase receptors including VEGF receptor 2 (VEGFR-2),IGF-1R, fibroblast GF-1R and epidermal GFR. We investigated the effectof MAE 87 in vivo using the mouse model for oxygen induced retinopathy.Methods: From postnatal day seven (P7) on, C57BL/6J mice were keptin a 75% oxygen environment for five days. On postnatal day 12 (P12)they received an intravitreal injection of MAE 87 in one eye and controlsubstance in the fellow eye. The animals were sacrificed by intracardialperfusion with fluorescein-dextran solution on P17. Retinal whole mountswere prepared and ischemic retinopathy was evaluated in 26 animals usinga standardized retinopathy score.Results: After a single intravitreal injection of MAE 87 there weresignificantly less angioproliferative changes (blood vessel tufts,extra-retinal neovascularization, and blood vessel tortuosity) than inthe fellow eye (p=0.007). The median retinopathy score (maximal 13) forthe MAE 87 treated eyes was 6 (25th percentile: 5; 75thpercentile: 7) and 8 for the control eyes (25th percentile: 5;75th percentile: 10).Conclusions: The tyrosine kinase inhibitor MAE 87 may be a promisingsubstance for local treatment of retinal neovascularization. Due to itsability to inhibit not only the VEGF but also the IGF-1 cascade, MAE 87may prove especially valuable for the treatment of diabeticretinopathy.

[学科分类] 生物化学/生物物理