A brain-derived neurotrophic factor mimetic is sufficient to restore cone photoreceptor visual function in an inherited blindness model

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Title: A brain-derived neurotrophic factor mimetic is sufficient to restore cone photoreceptor visual function in an inherited blindness model
Authors: Daly, Conor
Shine, Lisa
Heffernan, Theresa
Deeti, Sudhakar
Reynolds, Alison
O'Connor, J. J.
Dillon, Eugène T.
Duffy, David J.
Kolch, Walter
Cagney, Gerard
Kennedy, Breandán
Permanent link: http://hdl.handle.net/10197/9120
Date: 12-Sep-2017
Abstract: Controversially, histone deacetylase inhibitors (HDACi) are in clinical trial for the treatment of inherited retinal degeneration. Utilizing the zebrafish dyeucd6 model, we determined if treatment with HDACi can rescue cone photoreceptor-mediated visual function. dye exhibit defective visual behaviour and retinal morphology including ciliary marginal zone (CMZ) cell death and decreased photoreceptor outer segment (OS) length, as well as gross morphological defects including hypopigmentation and pericardial oedema. HDACi treatment of dye results in significantly improved optokinetic (OKR) (~43 fold, p < 0.001) and visualmotor (VMR) (~3 fold, p < 0.05) responses. HDACi treatment rescued gross morphological defects and reduced CMZ cell death by 80%. Proteomic analysis of dye eye extracts suggested BDNF-TrkB and Akt signaling as mediators of HDACi rescue inour dataset. Cotreatment with the TrkB antagonist ANA-12 blocked HDACi rescue of visual function and associated Akt phosphorylation. Notably, sole treatment with a BDNF mimetic, 7,8-dihydroxyflavone hydrate, significantly rescued dye visual function (~58 fold increase in OKR, p < 0.001, ~3 fold increase in VMR, p < 0.05). In summary, HDACi and a BDNF mimetic are sufficient to rescue retinal cell death and visual function in a vertebrate model of inherited blindness.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Springer
Journal: Scientific Reports
Volume: 7
Copyright (published version): 2017 the Authors
Keywords: Hereditary eye diseaseMechanisms of diseaseNeurodegneration
DOI: 10.1038/s41598-017-11513-5
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Biomolecular and Biomedical Science Research Collection
Medicine Research Collection

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