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Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental mo...

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Autores principales: Gaja-Capdevila, Núria, Hernández, Neus, Navarro, Xavier, Herrando-Grabulosa, Mireia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8702863/
https://www.ncbi.nlm.nih.gov/pubmed/34955848
http://dx.doi.org/10.3389/fphar.2021.780588
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author Gaja-Capdevila, Núria
Hernández, Neus
Navarro, Xavier
Herrando-Grabulosa, Mireia
author_facet Gaja-Capdevila, Núria
Hernández, Neus
Navarro, Xavier
Herrando-Grabulosa, Mireia
author_sort Gaja-Capdevila, Núria
collection PubMed
description Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental models of degenerative diseases and, importantly, mutations in the Sig-1R gene cause several types of motoneuron disease (MND). In this study we compared the potential therapeutic effect of three Sig-1R ligands, the agonists PRE-084 and SA4503 and the antagonist BD1063, in the SOD1(G93A) mouse model of ALS. Pharmacological administration was from 8 to 16 weeks of age, and the neuromuscular function and disease progression were evaluated using nerve conduction and rotarod tests. At the end of follow up (16 weeks), samples were harvested for histological and molecular analyses. The results showed that PRE-084, as well as BD1063 treatment was able to preserve neuromuscular function of the hindlimbs and increased the number of surviving MNs in the treated female SOD1(G93A) mice. SA4503 tended to improve motor function and preserved neuromuscular junctions (NMJ), but did not improve MN survival. Western blot analyses revealed that the autophagic flux and the endoplasmic reticulum stress, two pathways implicated in the physiopathology of ALS, were not modified with Sig-1R treatments in SOD1(G93A) mice. In conclusion, Sig-1R ligands are promising tools for ALS treatment, although more research is needed to ascertain their mechanisms of action.
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spelling pubmed-87028632021-12-25 Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice Gaja-Capdevila, Núria Hernández, Neus Navarro, Xavier Herrando-Grabulosa, Mireia Front Pharmacol Pharmacology Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental models of degenerative diseases and, importantly, mutations in the Sig-1R gene cause several types of motoneuron disease (MND). In this study we compared the potential therapeutic effect of three Sig-1R ligands, the agonists PRE-084 and SA4503 and the antagonist BD1063, in the SOD1(G93A) mouse model of ALS. Pharmacological administration was from 8 to 16 weeks of age, and the neuromuscular function and disease progression were evaluated using nerve conduction and rotarod tests. At the end of follow up (16 weeks), samples were harvested for histological and molecular analyses. The results showed that PRE-084, as well as BD1063 treatment was able to preserve neuromuscular function of the hindlimbs and increased the number of surviving MNs in the treated female SOD1(G93A) mice. SA4503 tended to improve motor function and preserved neuromuscular junctions (NMJ), but did not improve MN survival. Western blot analyses revealed that the autophagic flux and the endoplasmic reticulum stress, two pathways implicated in the physiopathology of ALS, were not modified with Sig-1R treatments in SOD1(G93A) mice. In conclusion, Sig-1R ligands are promising tools for ALS treatment, although more research is needed to ascertain their mechanisms of action. Frontiers Media S.A. 2021-12-10 /pmc/articles/PMC8702863/ /pubmed/34955848 http://dx.doi.org/10.3389/fphar.2021.780588 Text en Copyright © 2021 Gaja-Capdevila, Hernández, Navarro and Herrando-Grabulosa. 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
Gaja-Capdevila, Núria
Hernández, Neus
Navarro, Xavier
Herrando-Grabulosa, Mireia
Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice
title Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice
title_full Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice
title_fullStr Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice
title_full_unstemmed Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice
title_short Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice
title_sort sigma-1 receptor is a pharmacological target to promote neuroprotection in the sod1(g93a) als mice
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8702863/
https://www.ncbi.nlm.nih.gov/pubmed/34955848
http://dx.doi.org/10.3389/fphar.2021.780588
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