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Intravitreal Administration of rhNGF Enhances Regenerative Processes in a Zebrafish Model of Retinal Degeneration

Nerve growth factor (NGF) is the best characterized neurotrophin, and it is known to play an important role in ocular homeostasis. Here, we demonstrated the expression of NGF receptors in adult zebrafish retina and optimized a light-induced retina degeneration (LID) zebrafish model that mimics human...

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Autores principales: Cocchiaro, Pasquale, Di Donato, Vincenzo, Rubbini, Davide, Mastropasqua, Rodolfo, Allegretti, Marcello, Mantelli, Flavio, Aramini, Andrea, Brandolini, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8940169/
https://www.ncbi.nlm.nih.gov/pubmed/35330834
http://dx.doi.org/10.3389/fphar.2022.822359
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author Cocchiaro, Pasquale
Di Donato, Vincenzo
Rubbini, Davide
Mastropasqua, Rodolfo
Allegretti, Marcello
Mantelli, Flavio
Aramini, Andrea
Brandolini, Laura
author_facet Cocchiaro, Pasquale
Di Donato, Vincenzo
Rubbini, Davide
Mastropasqua, Rodolfo
Allegretti, Marcello
Mantelli, Flavio
Aramini, Andrea
Brandolini, Laura
author_sort Cocchiaro, Pasquale
collection PubMed
description Nerve growth factor (NGF) is the best characterized neurotrophin, and it is known to play an important role in ocular homeostasis. Here, we demonstrated the expression of NGF receptors in adult zebrafish retina and optimized a light-induced retina degeneration (LID) zebrafish model that mimics human cone-rod disorders, demonstrating that intravitreal (IV) administration of rhNGF can boost zebrafish retinal regeneration in this model. Adult zebrafish retinae exposed to 60 h of light irradiation (60 h LID) displayed evident reduction of outer nuclear layer (ONL) thickness and cell number with presence of apoptotic cells. Retinal histologic evaluation at different time points showed that IV therapeutic injection of rhNGF resulted in an increase of ONL thickness and cell number at late time points after damage (14 and 21 days post injury), ultimately accelerating retinal tissue recovery by driving retinal cell proliferation. At a molecular level, rhNGF activated the ERK1/2 pathway and enhanced the regenerative potential of Müller glia gfap- and vim-expressing cells by stimulating at early time points the expression of the photoreceptor regeneration factor Drgal1-L2. Our results demonstrate the highly conserved nature of NGF canonical pathway in zebrafish and thus support the use of zebrafish models for testing new compounds with potential retinal regenerative properties. Moreover, the pro-regenerative effects of IV-injected NGF that we observed pave the way to further studies aimed at evaluating its effects also in mammals, in order to expedite the development of novel rhNGF-based therapeutic approaches for ophthalmological disorders.
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spelling pubmed-89401692022-03-23 Intravitreal Administration of rhNGF Enhances Regenerative Processes in a Zebrafish Model of Retinal Degeneration Cocchiaro, Pasquale Di Donato, Vincenzo Rubbini, Davide Mastropasqua, Rodolfo Allegretti, Marcello Mantelli, Flavio Aramini, Andrea Brandolini, Laura Front Pharmacol Pharmacology Nerve growth factor (NGF) is the best characterized neurotrophin, and it is known to play an important role in ocular homeostasis. Here, we demonstrated the expression of NGF receptors in adult zebrafish retina and optimized a light-induced retina degeneration (LID) zebrafish model that mimics human cone-rod disorders, demonstrating that intravitreal (IV) administration of rhNGF can boost zebrafish retinal regeneration in this model. Adult zebrafish retinae exposed to 60 h of light irradiation (60 h LID) displayed evident reduction of outer nuclear layer (ONL) thickness and cell number with presence of apoptotic cells. Retinal histologic evaluation at different time points showed that IV therapeutic injection of rhNGF resulted in an increase of ONL thickness and cell number at late time points after damage (14 and 21 days post injury), ultimately accelerating retinal tissue recovery by driving retinal cell proliferation. At a molecular level, rhNGF activated the ERK1/2 pathway and enhanced the regenerative potential of Müller glia gfap- and vim-expressing cells by stimulating at early time points the expression of the photoreceptor regeneration factor Drgal1-L2. Our results demonstrate the highly conserved nature of NGF canonical pathway in zebrafish and thus support the use of zebrafish models for testing new compounds with potential retinal regenerative properties. Moreover, the pro-regenerative effects of IV-injected NGF that we observed pave the way to further studies aimed at evaluating its effects also in mammals, in order to expedite the development of novel rhNGF-based therapeutic approaches for ophthalmological disorders. Frontiers Media S.A. 2022-03-07 /pmc/articles/PMC8940169/ /pubmed/35330834 http://dx.doi.org/10.3389/fphar.2022.822359 Text en Copyright © 2022 Cocchiaro, Di Donato, Rubbini, Mastropasqua, Allegretti, Mantelli, Aramini and Brandolini. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Cocchiaro, Pasquale
Di Donato, Vincenzo
Rubbini, Davide
Mastropasqua, Rodolfo
Allegretti, Marcello
Mantelli, Flavio
Aramini, Andrea
Brandolini, Laura
Intravitreal Administration of rhNGF Enhances Regenerative Processes in a Zebrafish Model of Retinal Degeneration
title Intravitreal Administration of rhNGF Enhances Regenerative Processes in a Zebrafish Model of Retinal Degeneration
title_full Intravitreal Administration of rhNGF Enhances Regenerative Processes in a Zebrafish Model of Retinal Degeneration
title_fullStr Intravitreal Administration of rhNGF Enhances Regenerative Processes in a Zebrafish Model of Retinal Degeneration
title_full_unstemmed Intravitreal Administration of rhNGF Enhances Regenerative Processes in a Zebrafish Model of Retinal Degeneration
title_short Intravitreal Administration of rhNGF Enhances Regenerative Processes in a Zebrafish Model of Retinal Degeneration
title_sort intravitreal administration of rhngf enhances regenerative processes in a zebrafish model of retinal degeneration
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8940169/
https://www.ncbi.nlm.nih.gov/pubmed/35330834
http://dx.doi.org/10.3389/fphar.2022.822359
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