Investigative ophthalmology & visual science · 2020
A Clinical Metabolite of Azidothymidine Inhibits Experimental Choroidal Neovascularization and Retinal Pigmented Epithelium Degeneration.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Narendran Siddharth, Pereira Felipe, Yerramothu Praveen, Apicella Ivana, Wang Shao-Bin, Varshney Akhil, Baker Kirstie L, Marion Kenneth M, Ambati Meenakshi, Ambati Vidya L, Ambati Kameshwari, Sadda Srinivas R, Gelfand Bradley D, Ambati Jayakrishna
Аннотация
PURPOSE: Azidothymidine (AZT), a nucleoside reverse transcriptase inhibitor, possesses anti-inflammatory and anti-angiogenic activity independent of its ability to inhibit reverse transcriptase. The aim of this study was to evaluate the efficacy of 5'-glucuronyl azidothymidine (GAZT), an antiretrovirally inert hepatic clinical metabolite of AZT, in mouse models of retinal pigment epithelium (RPE) degeneration and choroidal neovascularization (CNV), hallmark features of dry and wet age-related macular degeneration (AMD), respectively.
METHODS: RPE degeneration was induced in wild-type (WT) C57BL/6J mice by subretinal injection of Alu RNA. RPE degeneration was assessed by fundus photography and confocal microscopy of zonula occludens-1-stained RPE flat mounts. Choroidal neovascularization was induced by laser injury in WT mice, and CNV volume was measured by confocal microscopy. AZT and GAZT were delivered by intravitreous injections. Inflammasome activation was monitored by western blotting for caspase-1 and by ELISA for IL-1β in Alu RNA-treated bone marrow-derived macrophages (BMDMs).
RESULTS: GAZT inhibited Alu RNA-induced RPE degeneration and laser-induced CNV. GAZT also reduced Alu RNA-induced caspase-1 activation and IL-1β release in BMDMs.
CONCLUSIONS: GAZT possesses dual anti-inflammatory and anti-angiogenic properties and could be a viable treatment option for both forms of AMD.
METHODS: RPE degeneration was induced in wild-type (WT) C57BL/6J mice by subretinal injection of Alu RNA. RPE degeneration was assessed by fundus photography and confocal microscopy of zonula occludens-1-stained RPE flat mounts. Choroidal neovascularization was induced by laser injury in WT mice, and CNV volume was measured by confocal microscopy. AZT and GAZT were delivered by intravitreous injections. Inflammasome activation was monitored by western blotting for caspase-1 and by ELISA for IL-1β in Alu RNA-treated bone marrow-derived macrophages (BMDMs).
RESULTS: GAZT inhibited Alu RNA-induced RPE degeneration and laser-induced CNV. GAZT also reduced Alu RNA-induced caspase-1 activation and IL-1β release in BMDMs.
CONCLUSIONS: GAZT possesses dual anti-inflammatory and anti-angiogenic properties and could be a viable treatment option for both forms of AMD.
Предметные рубрики MeSH
AnimalsBlotting, WesternCaspase 1Choroidal NeovascularizationDisease Models, AnimalEnzyme-Linked Immunosorbent AssayFemaleGeographic AtrophyInterleukin-1betaIntravitreal InjectionsMacrophagesMaleMiceMice, Inbred C57BLMicroscopy, ConfocalRetinal Pigment EpitheliumReverse Transcriptase InhibitorsZidovudineZonula Occludens-1 Protein