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Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss

Here, we have blocked the signaling pathway of tumor necrosis factor α (TNFα) in a mouse model of traumatic neuropathy using a small cell permeable molecule (R7050) that inhibits TNFα/TNF receptor 1 (TNFR1) complex internalization. Adult pigmented mice were subjected to intraorbital optic nerve crus...

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Autores principales: Lucas-Ruiz, Fernando, Galindo-Romero, Caridad, Salinas-Navarro, Manuel, González-Riquelme, María Josefa, Vidal-Sanz, Manuel, Agudo Barriuso, Marta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803525/
https://www.ncbi.nlm.nih.gov/pubmed/31680831
http://dx.doi.org/10.3389/fnins.2019.01096
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author Lucas-Ruiz, Fernando
Galindo-Romero, Caridad
Salinas-Navarro, Manuel
González-Riquelme, María Josefa
Vidal-Sanz, Manuel
Agudo Barriuso, Marta
author_facet Lucas-Ruiz, Fernando
Galindo-Romero, Caridad
Salinas-Navarro, Manuel
González-Riquelme, María Josefa
Vidal-Sanz, Manuel
Agudo Barriuso, Marta
author_sort Lucas-Ruiz, Fernando
collection PubMed
description Here, we have blocked the signaling pathway of tumor necrosis factor α (TNFα) in a mouse model of traumatic neuropathy using a small cell permeable molecule (R7050) that inhibits TNFα/TNF receptor 1 (TNFR1) complex internalization. Adult pigmented mice were subjected to intraorbital optic nerve crush (ONC). Animals received daily intraperitoneal injections of R7050, and/or a single intravitreal administration the day of the surgery. Some animals received a combinatorial treatment with R7050 (systemic or local) and a single intravitreal injection of brain derived neurotrophic factor (BDNF). As controls, untreated animals were used. Retinas were analyzed for RGC survival 5 and 14 days after the lesion i.e., during the quick and slow phase of axotomy-induced RGC death. qPCR analyses were done to verify that Tnfr1 and TNFα were up-regulated after ONC. At 5 days post-lesion, R7050 intravitreal or systemic treatment neuroprotected RGCs as much as BDNF alone. At 14 days, RGC rescue by systemic or intravitreal administration of R7050 was similar. At this time point, intravitreal treatment with BDNF was significantly better than intravitreal R7050. Combinatory treatment was not better than BDNF alone, although at both time points, the mean number of surviving RGCs was higher. In conclusion, antagonism of the extrinsic pathway of apoptosis rescues axotomized RGCs as it does the activation of survival pathways by BDNF. However, manipulation of both pathways at the same time, does not improve RGC survival.
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spelling pubmed-68035252019-11-03 Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss Lucas-Ruiz, Fernando Galindo-Romero, Caridad Salinas-Navarro, Manuel González-Riquelme, María Josefa Vidal-Sanz, Manuel Agudo Barriuso, Marta Front Neurosci Neuroscience Here, we have blocked the signaling pathway of tumor necrosis factor α (TNFα) in a mouse model of traumatic neuropathy using a small cell permeable molecule (R7050) that inhibits TNFα/TNF receptor 1 (TNFR1) complex internalization. Adult pigmented mice were subjected to intraorbital optic nerve crush (ONC). Animals received daily intraperitoneal injections of R7050, and/or a single intravitreal administration the day of the surgery. Some animals received a combinatorial treatment with R7050 (systemic or local) and a single intravitreal injection of brain derived neurotrophic factor (BDNF). As controls, untreated animals were used. Retinas were analyzed for RGC survival 5 and 14 days after the lesion i.e., during the quick and slow phase of axotomy-induced RGC death. qPCR analyses were done to verify that Tnfr1 and TNFα were up-regulated after ONC. At 5 days post-lesion, R7050 intravitreal or systemic treatment neuroprotected RGCs as much as BDNF alone. At 14 days, RGC rescue by systemic or intravitreal administration of R7050 was similar. At this time point, intravitreal treatment with BDNF was significantly better than intravitreal R7050. Combinatory treatment was not better than BDNF alone, although at both time points, the mean number of surviving RGCs was higher. In conclusion, antagonism of the extrinsic pathway of apoptosis rescues axotomized RGCs as it does the activation of survival pathways by BDNF. However, manipulation of both pathways at the same time, does not improve RGC survival. Frontiers Media S.A. 2019-10-15 /pmc/articles/PMC6803525/ /pubmed/31680831 http://dx.doi.org/10.3389/fnins.2019.01096 Text en Copyright © 2019 Lucas-Ruiz, Galindo-Romero, Salinas-Navarro, González-Riquelme, Vidal-Sanz and Agudo Barriuso. http://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 Neuroscience
Lucas-Ruiz, Fernando
Galindo-Romero, Caridad
Salinas-Navarro, Manuel
González-Riquelme, María Josefa
Vidal-Sanz, Manuel
Agudo Barriuso, Marta
Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss
title Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss
title_full Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss
title_fullStr Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss
title_full_unstemmed Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss
title_short Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss
title_sort systemic and intravitreal antagonism of the tnfr1 signaling pathway delays axotomy-induced retinal ganglion cell loss
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803525/
https://www.ncbi.nlm.nih.gov/pubmed/31680831
http://dx.doi.org/10.3389/fnins.2019.01096
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