Abstract
Purpose:
We evaluated the effects of BIBF1120, a novel triple angiokinase inhibitor against pathological retinal neovascularization, using a model of ischemic oxygen-induced retinopathy (OIR).
Methods:
BIBF1120 effect on development of the normal retinal vasculature was evaluated in Sprague-Dawley rat pups (n=8 per group) intravitreally (IV) injected with different concentrations of BIBF1120 or vehicle (PBS) at postnatal day (P) P2 and analyzed at P7. Two models of OIR and the aortic ring assay were used to assess the antiangiogenic effects of BIBF1120. In the vasoobliteration model (VO), rat pups exposed to 80% O2 from P5 to 10 were injected IV at P5 and evaluated at P10. In the pre-retinal neovascularization model (NV), rat pups were exposed to cycling O2 [50% and 10% alternated q24 h] from P1-P14 followed by room air until P18. Animals received twice IV injections (1 µl) of BIBF1120 or vehicle (PBS) on P5 and P12. Retinal vasculature, VO, and NV were assessed by using retinal flat-mounts stained with lectins. Retinal expression of VEGF, Netrin-1, EphrinB2 and Ephrin receptor B4 (EphB4) was analyzed in the OIR-NV model by qPCR.
Results:
BIBF1120 dose-dependently interfered with normal retinal vascular development and microvessel branching in the aortic assay, as anticipated. However in OIR, BIBF1120 did not accrue vasoobliteration when studied between P5 and P10. On the contrary, BIBF1120 accelerated normal retinal revascularisation and robustly diminished pre-retinal neovascularisation compared to vehicle (by >50%). To explain the latter we surmised a modulation of BIBF1120 on VEGF and neural guidance cues and their receptors, such as ephrins and netrins, which function as angiogenic regulators in the retina. As anticipated the expression levels of VEGF, Netrin-1, EphrinB2 and EphB4 mRNA in the retina of OIR animals were highly increased compared to normoxia. VEGF, Netrin-1, and EphB4 but not EphrinB2 mRNA was decreased significantly (p<0,05) by BIBF1120 treatment compared to control.
Conclusions:
Data reveal efficacy of BIBF1120 on pre-retinal neovascularization and of greater interest on acceleration of normal revascularization, possibly by interfering with major repulsive cues expressed in the retina during OIR. Hence, BIBF1120 appears to exhibit preferable properties compared to anti-VEGF therapies for the treatment of ischemic retinopathies.
Keywords: 700 retinal neovascularization •
706 retinopathy of prematurity •
543 growth factors/growth factor receptors