Abstract
Corneal neovascularization (CNV) causes higher-order aberrations, corneal edema, ocular inflammation, and corneal transplant rejection, thereby decreasing visual acuity. In this study, we investigated the effects of topical administration of the kappa opioid receptor agonist nalfurafine (TRK-820) on CNV. To induce CNV, intrastromal corneal sutures were placed on the corneal stroma of BALB/c mice for 2 weeks. Nalfurafine (0.1 µg/2 μL/eye) was topically administered to the cornea once or twice daily after CNV induction. The CNV score, immune cell infiltration, and mRNA levels of angiogenic and pro-inflammatory factors in neovascularized corneas were evaluated using slit-lamp microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction. The mRNA expression of the kappa opioid receptor gene Oprk1 was significantly upregulated following CNV induction. Topical administration of nalfurafine twice daily significantly suppressed CNV and lymphangiogenesis, as well as reduced the mRNA levels of angiogenic and pro-inflammatory factors in the neovascularized corneas. Moreover, nalfurafine administration twice daily reduced the numbers of infiltrating leukocytes, neutrophils, macrophages, and interferon-γ-producing CD4+ T cells in the neovascularized corneas. In this study, we demonstrated that topical administration of nalfurafine suppressed local CNV in a mouse model along with the activation of KOR, suggesting that nalfurafine may prevent and control CNV in humans.
Highlights
Corneal neovascularization (CNV) causes higher-order aberrations, corneal edema, ocular inflammation, and corneal transplant rejection, thereby decreasing visual acuity
To investigate the effects of CNV induced by suture knots in the central cornea, mRNA levels of angiogenic, lymphangiogenic, and inflammatory factors in the neovascularized tissue were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) on days 7 and 14 post neovascularization induction
Vegfa and Vegfc mRNA levels were significantly increased at days 7 and 14 post neovascularization induction compared to the level in control (Fig. 1e,f; n = 3, P < 0.001). mRNA levels of Flt[1] that encodes VEGFR-1 were significantly increased only at day 14 post neovascularization induction compared to the control level (Fig. 1g, n = 3, P = 0.049)
Summary
Corneal neovascularization (CNV) causes higher-order aberrations, corneal edema, ocular inflammation, and corneal transplant rejection, thereby decreasing visual acuity. We investigated the effects of topical administration of the kappa opioid receptor agonist nalfurafine (TRK-820) on CNV. Topical administration of nalfurafine twice daily significantly suppressed CNV and lymphangiogenesis, as well as reduced the mRNA levels of angiogenic and pro-inflammatory factors in the neovascularized corneas. Recent studies in human umbilical vein endothelial cells have revealed anti-angiogenic effects of the KOR agonists U50, 4 88H12 and nalfurafine (TRK-820)[13,14,15], mediated by the suppression of the VEGFR expression[16]. In this study, we investigated the anti-angiogenic effects of the topically administered KOR agonist nalfurafine in a murine CNV model
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