Growth inhibition of formed corneal neovascularization following Fosaprepitant treatment

Abstract

Purpose: The aim of this study was to test the efficacy of Neurokinin-1 Receptor (NK-1R) antagonist -Fosaprepitant- in inducing regression of established corneal neovascularization (CNV).

Methods: Twenty C57BL/6 mice underwent alkali burn. Seven days later, when corneal neovessels had developed, they received Fosaprepitant 10 mg/ml, administered topically six times a day in the right eye for 10 days. In parallel, a group of 20 causticated mice was treated with normal saline, as control. A second independent experiment was also performed (n = 10/group). Finally, ten healthy mice received the same topical treatment for 10 days to evaluate Fosaprepitant safety. Haemangiogenesis and lymphangiogenesis were measured by means of vesselj plugin (imagej). Secondary endpoints, such as leucocyte infiltration, corneal opacity and corneal fluorescein staining were also evaluated. Inflammatory cell composition was assessed by flow cytometry. Differences between groups were assessed using unpaired t-test, Mann-Whitney U-test or two-way anova, as appropriate.

Results: Topical Fosaprepitant administration induced a significant reduction of (i) CD31⁺ blood corneal neovessels (-27%, p = 0.0132), (ii) LYVE1⁺ lymphatic corneal neovessels (-31%, p = 0.0118) and (iii) CD45⁺ leucocyte infiltration (-36%; p = 0.0237). The second independent experiment confirmed these data. Moreover, Fosaprepitant-treated corneas showed a reduction in opacity, no impairment in corneal fluorescein staining and decreased infiltration of neutrophils (-72%, p < 0.05) and macrophages (-75%, p < 0.01). Finally, topical Fosaprepitant was not toxic to the ocular surface: no signs of conjunctivitis, opacity, perforations or corneal fluorescein staining were detected. Similarly, corneal TUJ1⁺ nerve density was not affected.

Conclusions: Our data suggest that NK-1R antagonists, such as Fosaprepitant, could be a new, promising therapeutic tool to inhibit CNV after this has been established.

Keywords: Fosaprepitant; NK-1 receptor antagonist; Substance P; corneal neovascularization.