Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation
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 (TR...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-88118-6 |
| _version_ | 1818842801834557440 |
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| author | Hurramhon Shokirova Takenori Inomata Tsuyoshi Saitoh Jun Zhu Kenta Fujio Yuichi Okumura Ai Yanagawa Keiichi Fujimoto Jaemyoung Sung Atsuko Eguchi Maria Miura Ken Nagino Kunihiko Hirosawa Mizu Kuwahara Yasutsugu Akasaki Hiroshi Nagase Akira Murakami |
| author_facet | Hurramhon Shokirova Takenori Inomata Tsuyoshi Saitoh Jun Zhu Kenta Fujio Yuichi Okumura Ai Yanagawa Keiichi Fujimoto Jaemyoung Sung Atsuko Eguchi Maria Miura Ken Nagino Kunihiko Hirosawa Mizu Kuwahara Yasutsugu Akasaki Hiroshi Nagase Akira Murakami |
| author_sort | Hurramhon Shokirova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T04:47:45Z |
| format | Article |
| id | doaj.art-3ae6a01079114237a7e64390f3ffeccb |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:47:45Z |
| publishDate | 2021-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3ae6a01079114237a7e64390f3ffeccb2022-12-21T20:35:26ZengNature PortfolioScientific Reports2045-23222021-04-0111111510.1038/s41598-021-88118-6Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammationHurramhon Shokirova0Takenori Inomata1Tsuyoshi Saitoh2Jun Zhu3Kenta Fujio4Yuichi Okumura5Ai Yanagawa6Keiichi Fujimoto7Jaemyoung Sung8Atsuko Eguchi9Maria Miura10Ken Nagino11Kunihiko Hirosawa12Mizu Kuwahara13Yasutsugu Akasaki14Hiroshi Nagase15Akira Murakami16Department of Ophthalmology, Juntendo University Graduate School of MedicineDepartment of Ophthalmology, Juntendo University Graduate School of MedicineInternational Institute for Integrative Sleep Medicine (WPI-IIIS), University of TsukubaDepartment of Ophthalmology, Juntendo University Graduate School of MedicineDepartment of Ophthalmology, Juntendo University Graduate School of MedicineDepartment of Ophthalmology, Juntendo University Graduate School of MedicineDepartment of Digital Medicine, Juntendo University Graduate School of MedicineDepartment of Ophthalmology, Juntendo University Faculty of MedicineDepartment of Ophthalmology, Juntendo University Graduate School of MedicineDepartment of Hospital Administration, Juntendo University Graduate School of MedicineDepartment of Ophthalmology, Juntendo University Graduate School of MedicineDepartment of Hospital Administration, Juntendo University Graduate School of MedicineDepartment of Ophthalmology, Juntendo University Graduate School of MedicineDepartment of Ophthalmology, Juntendo University Graduate School of MedicineDepartment of Ophthalmology, Juntendo University Graduate School of MedicineInternational Institute for Integrative Sleep Medicine (WPI-IIIS), University of TsukubaDepartment of Ophthalmology, Juntendo University Graduate School of MedicineAbstract 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.https://doi.org/10.1038/s41598-021-88118-6 |
| spellingShingle | Hurramhon Shokirova Takenori Inomata Tsuyoshi Saitoh Jun Zhu Kenta Fujio Yuichi Okumura Ai Yanagawa Keiichi Fujimoto Jaemyoung Sung Atsuko Eguchi Maria Miura Ken Nagino Kunihiko Hirosawa Mizu Kuwahara Yasutsugu Akasaki Hiroshi Nagase Akira Murakami Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation Scientific Reports |
| title | Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation |
| title_full | Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation |
| title_fullStr | Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation |
| title_full_unstemmed | Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation |
| title_short | Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation |
| title_sort | topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation |
| url | https://doi.org/10.1038/s41598-021-88118-6 |
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