Long-Term Protection of Genetically Ablated Rabbit Retinal Degeneration by Sustained Transscleral Unoprostone Delivery

Autor: Aya Katsuyama, Mineo Kondo, Eri Koyanagi, Nobuhiro Nagai, Toshiaki Abe, Noriko Osumi, Hirokazu Kaji, Yukihiko Mashima, Hiroko Terasaki, Matsuhiko Nishizawa, Toru Nakazawa, Yasuko Izumida, Junjun Liu
Rok vydání: 2016
Předmět:
0301 basic medicine
Retinal degeneration
Time Factors
genetic structures
DNA Mutational Analysis
Dinoprost
Animals
Genetically Modified
chemistry.chemical_compound
0302 clinical medicine
In Situ Hybridization
Drug Implants
medicine.diagnostic_test
Reverse Transcriptase Polymerase Chain Reaction
Retinal Degeneration
Anatomy
Immunohistochemistry
medicine.anatomical_structure
Rabbits
Erg
Sclera
Tomography
Optical Coherence
medicine.drug
Rhodopsin
medicine.medical_specialty
Biology
Retina
Aqueous Humor
03 medical and health sciences
Unoprostone Isopropyl
Ophthalmology
Electroretinography
medicine
Animals
Large-Conductance Calcium-Activated Potassium Channels
Choroid
Retinal
DNA
medicine.disease
eye diseases
Disease Models
Animal
030104 developmental biology
Gene Expression Regulation
Unoprostone
chemistry
Delayed-Action Preparations
Mutation
030221 ophthalmology & optometry
sense organs
Chromatography
Liquid
Follow-Up Studies
Zdroj: Investigative Opthalmology & Visual Science. 57:6527
ISSN: 1552-5783
DOI: 10.1167/iovs.16-20453
Popis: Purpose To evaluate the long-term protective effects of transscleral unoprostone (UNO) against retinal degeneration in transgenic (Tg) rabbits (Pro347Leu rhodopsin mutation). Methods The UNO release devices (URDs) were implanted into the sclerae of Tg rabbits and ERG, optical coherence tomography (OCT), and ophthalmic examinations were conducted for 40 weeks. Unoprostone metabolites in retina, choroid/RPE, aqueous humor, and plasma from wild-type (Wt) rabbits were measured using liquid chromatography-tandem mass spectrometry. In situ hybridization and immunohistochemistry evaluated the retinal distribution of big potassium (BK) channels, and RT-PCR evaluated the expressions of BK channels and m-opsin at 1 week after URD treatment. Results The URD released UNO at a rate of 10.2 ±1.0 μg/d, and the release rate and amount of UNO decreased during 32 weeks. Higher ERG amplitudes were observed in the URD-treated Tg rabbits compared with the placebo-URD, or nontreated controls. At 24 weeks after implantation into the URD-treated Tg rabbits, OCT images showed preservation of retinal thickness, and histologic examinations (44 weeks) showed greater thickness of outer nuclear layers. Unoprostone was detected in the retina, choroid, and plasma of Wt rabbits. Retina/plasma ratio of UNO levels were 38.0 vs. 0.68 ng UNO*hour/mL in the URD-treated group versus control (topical UNO), respectively. Big potassium channels were observed in cone, cone ON-bipolar, and rod bipolar cells. Reverse-transcriptase PCR demonstrated BK channels and m-opsins increased in URD-treated eyes. Conclusions In Tg rabbits, URD use slowed the decline of retinal function for more than 32 weeks, and therefore provides a promising tool for long-term treatment of RP.
Databáze: OpenAIRE
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