Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy
Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in...
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doaj-1ac4a18e45a64c96a8cacd785255ca9e2021-08-26T14:12:39ZengMDPI AGPharmaceutics1999-49232021-07-01131105110510.3390/pharmaceutics13081105Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic RetinopathyCecile Lebon0Heike Neubauer1Marianne Berdugo2Kimberley Delaunay3Elke Markert4Kolja Becker5Katja S. Baum-Kroker6Jürgen Prestle7Holger Fuchs8Remko A. Bakker9Francine Behar-Cohen10Team 17: Physiopathology of Ocular Diseases: Therapeutic Innovations, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, FranceCardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, GermanyTeam 17: Physiopathology of Ocular Diseases: Therapeutic Innovations, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, FranceTeam 17: Physiopathology of Ocular Diseases: Therapeutic Innovations, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, FranceGlobal Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, GermanyGlobal Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, GermanyDrug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, GermanyCardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, GermanyCardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, GermanyCardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, GermanyTeam 17: Physiopathology of Ocular Diseases: Therapeutic Innovations, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, FranceRho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, indicating that ROCK inhibition could be a promising new therapeutic approach for the treatment of diabetic retinopathy. However, due to its short intravitreal half-life, fasudil is not suitable for long-term treatment. In this study, we evaluated a very potent ROCK1/2 inhibitor (BIRKI) in a depot formulation administered as a single intravitreal injection providing a slow release for at least four weeks. Following BIRKI intravitreal injection in old Goto-Kakizaki (GK) type 2 diabetic rats, we observed a significant reduction in ROCK1 activity in the retinal pigment epithelium/choroid complex after 8 days and relocation of ROCK1 to the cytoplasm and nucleus in retinal pigment epithelium cells after 28 days. The chronic ROCK inhibition by the BIRKI depot formulation restored retinal pigment epithelial cell morphology and distribution, favored retinal capillaries dilation, and reduced hypoxia and inner blood barrier leakage observed in the diabetic retina. No functional or morphological negative effects were observed, indicating suitable tolerability of BIRKI after intravitreous injection. In conclusion, our data suggest that sustained ROCK inhibition, provided by BIRKI slow-release formulation, could be a valuable treatment option for diabetic retinopathy, especially with regard to the improvement of retinal vascular infusion and protection of the outer retinal barrier.https://www.mdpi.com/1999-4923/13/8/1105diabetic retinopathyrho-kinase inhibitorslow-release formulationretinal pigment epitheliumretinal hypoxiavasoconstriction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Cecile Lebon Heike Neubauer Marianne Berdugo Kimberley Delaunay Elke Markert Kolja Becker Katja S. Baum-Kroker Jürgen Prestle Holger Fuchs Remko A. Bakker Francine Behar-Cohen |
spellingShingle |
Cecile Lebon Heike Neubauer Marianne Berdugo Kimberley Delaunay Elke Markert Kolja Becker Katja S. Baum-Kroker Jürgen Prestle Holger Fuchs Remko A. Bakker Francine Behar-Cohen Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy Pharmaceutics diabetic retinopathy rho-kinase inhibitor slow-release formulation retinal pigment epithelium retinal hypoxia vasoconstriction |
author_facet |
Cecile Lebon Heike Neubauer Marianne Berdugo Kimberley Delaunay Elke Markert Kolja Becker Katja S. Baum-Kroker Jürgen Prestle Holger Fuchs Remko A. Bakker Francine Behar-Cohen |
author_sort |
Cecile Lebon |
title |
Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy |
title_short |
Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy |
title_full |
Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy |
title_fullStr |
Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy |
title_full_unstemmed |
Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy |
title_sort |
evaluation of an intravitreal rho-associated kinase inhibitor depot formulation in a rat model of diabetic retinopathy |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2021-07-01 |
description |
Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, indicating that ROCK inhibition could be a promising new therapeutic approach for the treatment of diabetic retinopathy. However, due to its short intravitreal half-life, fasudil is not suitable for long-term treatment. In this study, we evaluated a very potent ROCK1/2 inhibitor (BIRKI) in a depot formulation administered as a single intravitreal injection providing a slow release for at least four weeks. Following BIRKI intravitreal injection in old Goto-Kakizaki (GK) type 2 diabetic rats, we observed a significant reduction in ROCK1 activity in the retinal pigment epithelium/choroid complex after 8 days and relocation of ROCK1 to the cytoplasm and nucleus in retinal pigment epithelium cells after 28 days. The chronic ROCK inhibition by the BIRKI depot formulation restored retinal pigment epithelial cell morphology and distribution, favored retinal capillaries dilation, and reduced hypoxia and inner blood barrier leakage observed in the diabetic retina. No functional or morphological negative effects were observed, indicating suitable tolerability of BIRKI after intravitreous injection. In conclusion, our data suggest that sustained ROCK inhibition, provided by BIRKI slow-release formulation, could be a valuable treatment option for diabetic retinopathy, especially with regard to the improvement of retinal vascular infusion and protection of the outer retinal barrier. |
topic |
diabetic retinopathy rho-kinase inhibitor slow-release formulation retinal pigment epithelium retinal hypoxia vasoconstriction |
url |
https://www.mdpi.com/1999-4923/13/8/1105 |
work_keys_str_mv |
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