Local injection of receptor tyrosine kinase inhibitor MAE 87 reduces retinal neovascularization in mice.
OBJECTIVE
Retinal neovascularization occurs under the influence of angiogenic factors like vascular endothelial growth factor (VEGF). VEGF signaling is enhanced by insulin-like growth factor-1 (IGF-1). In vitro, the oxoindolinone MAE 87 inhibits angiogenic signal transduction by blocking tyrosine kinase receptors including VEGF receptor 2 (VEGFR-2), IGF-1R, fibroblast GF-1R and epidermal GFR. We investigated the effect of MAE 87 in vivo using the mouse model for oxygen induced retinopathy.


METHODS
From postnatal day seven (P7) on, C57BL/6J mice were kept in a 75% oxygen environment for five days. On postnatal day 12 (P12) they received an intravitreal injection of MAE 87 in one eye and control substance in the fellow eye. The animals were sacrificed by intracardial perfusion with fluorescein-dextran solution on P17. Retinal whole mounts were prepared and ischemic retinopathy was evaluated in 26 animals using a standardized retinopathy score.


RESULTS
After a single intravitreal injection of MAE 87 there were significantly less angioproliferative changes (blood vessel tufts, extra-retinal neovascularization, and blood vessel tortuosity) than in the fellow eye (p=0.007). The median retinopathy score (maximal 13) for the MAE 87 treated eyes was 6 (25th percentile: 5; 75th percentile: 7) and 8 for the control eyes (25th percentile: 5; 75th percentile: 10).


CONCLUSIONS
The tyrosine kinase inhibitor MAE 87 may be a promising substance for local treatment of retinal neovascularization. Due to its ability to inhibit not only the VEGF but also the IGF-1 cascade, MAE 87 may prove especially valuable for the treatment of diabetic retinopathy.
Unsoeld
Anke S
AS
Department of Ophthalmology, University of Freiburg, Freiburg, Germany.
Junker
Bernd
B
Mazitschek
Ralph
R
Martin
Gottfried
G
Hansen
Lutz L
LL
Giannis
Athanassios
A
Agostini
Hansjürgen T
HT
D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005451:Fluorescein Angiography; D018496:Hyperoxia / Q000150:complications; D007211:Indoles / Q000627:therapeutic use*; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000633:toxicity; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012160:Retina / Q000187:drug effects; D015861:Retinal Neovascularization / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology; D014822:Vitreous Body
D004791:Enzyme Inhibitors; D007211:Indoles; C488510:MAE 87; D020794:Receptor Protein-Tyrosine Kinases; D010100:Oxygen