Efficacy of Sunitinib, Sunitinib-Hesperetin, and Sunitinib-Doxycycline Combinations on Experimentally-Induced Corneal Neovascularization

Abstract

ABSTRACTPurpose: To investigate the preventive effects of topical sunitinib, sunitinib-hesperetin and sunitinib-doxycycline combinations on corneal neovascularization (CNV), apoptosis and fibrosis in a corneal alkali burn model.Materials and Methods: The corneas of 32 Wistar albino rats were cauterized with silver nitrate to induce CNV. Four groups were created receiving artificial tears (sham), sunitinib (0.5 mg/ml), sunitinib-hesperetin (0.5 mg/ml-0.2 mg/ml), and sunitinib-doxycycline (0.5 mg/ml-20 mg/ml) treatments. Corneal photographs were taken on days 0, 7 and 15‎. Photographs of the cornea were digitally analyzed to measure the size of the neovascularization area in comparison to the total corneal surface area. On the 15th day, the animals were euthanized, and the eyes were enucleated for immunohistochemical staining to investigate neovascularization, apoptosis, and fibrosis.Results: CNV areas on the 7th day in the sunitinib (4.8% ± 0.07%) and sunitinib-hesperetin (1.1% ± 0.03%) groups were smaller than those in the sham group (33.9% ± 0.12%) (p = 0.001 and, p < 0.001 respectively). On the 15th day, the CNV area in the sunitinib-hesperetin (20.8% ± 0.37%) group was significantly smaller than that of the sham group (74.6% ± 0.32%) (p = 0.039). The combination groups had lower levels of VEGF, TUNEL and α-SMA positivity than the sunitinib monotherapy group. TUNEL positivity was lowest in the sunitinib-hesperetin and sunitinib-doxycycline groups, and α-SMA positivity was lowest in the sunitinib-hesperetin group.Conclusion: Topical sunitinib-hesperetin was more effective than sunitinib alone and the sunitinib-doxycycline combination in the treatment of CNV. The combination of sunitinib and hesperetin seems to be a promising treatment for preventing corneal fibrosis and apoptosis.