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Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a...

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Autores principales: Gaja-Capdevila, Núria, Hernández, Neus, Zamanillo, Daniel, Vela, Jose Miguel, Merlos, Manuel, Navarro, Xavier, Herrando-Grabulosa, Mireia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269081/
https://www.ncbi.nlm.nih.gov/pubmed/34203381
http://dx.doi.org/10.3390/ijms22136956
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author Gaja-Capdevila, Núria
Hernández, Neus
Zamanillo, Daniel
Vela, Jose Miguel
Merlos, Manuel
Navarro, Xavier
Herrando-Grabulosa, Mireia
author_facet Gaja-Capdevila, Núria
Hernández, Neus
Zamanillo, Daniel
Vela, Jose Miguel
Merlos, Manuel
Navarro, Xavier
Herrando-Grabulosa, Mireia
author_sort Gaja-Capdevila, Núria
collection PubMed
description Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries.
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spelling pubmed-82690812021-07-10 Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice Gaja-Capdevila, Núria Hernández, Neus Zamanillo, Daniel Vela, Jose Miguel Merlos, Manuel Navarro, Xavier Herrando-Grabulosa, Mireia Int J Mol Sci Article Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries. MDPI 2021-06-28 /pmc/articles/PMC8269081/ /pubmed/34203381 http://dx.doi.org/10.3390/ijms22136956 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gaja-Capdevila, Núria
Hernández, Neus
Zamanillo, Daniel
Vela, Jose Miguel
Merlos, Manuel
Navarro, Xavier
Herrando-Grabulosa, Mireia
Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice
title Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice
title_full Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice
title_fullStr Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice
title_full_unstemmed Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice
title_short Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice
title_sort neuroprotective effects of sigma 1 receptor ligands on motoneuron death after spinal root injury in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269081/
https://www.ncbi.nlm.nih.gov/pubmed/34203381
http://dx.doi.org/10.3390/ijms22136956
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