EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration

Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that S...

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Autores: Gaja Capdevila, Núria|||0000-0002-0028-570X, Hernández, Neus, Yeste, Sandra, Reinoso, Raquel, Burgueño, Javier, Montero, Ana, Merlos, Manuel, Vela, José M., Herrando-Grabulosa, Mireia|||0000-0002-6685-3220, Navarro, X. (Xavier)|||0000-0001-9849-902X
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:260278
Acceso en línea:https://ddd.uab.cat/record/260278
https://dx.doi.org/urn:doi:10.3390/ijms23126737
Access Level:acceso abierto
Palabra clave:Amyotrophic lateral sclerosis
Motoneuron degeneration
Sigma-1 receptor
SOD1G93A mice
Spinal nerve injury
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spelling EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degenerationGaja Capdevila, Núria|||0000-0002-0028-570XHernández, NeusYeste, SandraReinoso, RaquelBurgueño, JavierMontero, AnaMerlos, ManuelVela, José M.Herrando-Grabulosa, Mireia|||0000-0002-6685-3220Navarro, X. (Xavier)|||0000-0001-9849-902XAmyotrophic lateral sclerosisMotoneuron degenerationSigma-1 receptorSOD1G93A miceSpinal nerve injuryMotor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that Sig-1R is a target to prevent MN degeneration. In this study, two novel synthesized Sig-1R ligands, coded EST79232 and EST79376, from the same chemical series, with the same scaffold and similar physicochemical properties but opposite functionality on Sig-1R, were evaluated as neuroprotective compounds to prevent MN degeneration. We used an in vitro model of spinal cord organotypic cultures under chronic excitotoxicity and two in vivo models, the spinal nerve injury and the superoxide dismutase 1 (SOD1)G93A mice, to characterize the effects of these Sig-1R ligands on MN survival and modulation of glial reactivity. The antagonist EST79376 preserved MNs in vitro and after spinal nerve injury but was not able to improve MN death in SOD1G93A mice. In contrast, the agonist EST79232 significantly increased MN survival in the three models of MN degeneration evaluated and had a mild beneficial effect on motor function in SOD1G93A mice. In vivo, Sig-1R ligand EST79232 had a more potent effect on preventing MN degeneration than EST79376. These data further support the interest in Sig-1R as a therapeutic target for neurodegeneration.Universitat Autònoma de Barcelona. Institut de Neurociències 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/260278https://dx.doi.org/urn:doi:10.3390/ijms23126737reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-096386-B-I00Ministerio de Sanidad y Consumo CB06/05/1105open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2602782026-06-06T12:50:31Z
dc.title.none.fl_str_mv EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
title EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
spellingShingle EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
Gaja Capdevila, Núria|||0000-0002-0028-570X
Amyotrophic lateral sclerosis
Motoneuron degeneration
Sigma-1 receptor
SOD1G93A mice
Spinal nerve injury
title_short EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
title_full EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
title_fullStr EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
title_full_unstemmed EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
title_sort EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
dc.creator.none.fl_str_mv Gaja Capdevila, Núria|||0000-0002-0028-570X
Hernández, Neus
Yeste, Sandra
Reinoso, Raquel
Burgueño, Javier
Montero, Ana
Merlos, Manuel
Vela, José M.
Herrando-Grabulosa, Mireia|||0000-0002-6685-3220
Navarro, X. (Xavier)|||0000-0001-9849-902X
author Gaja Capdevila, Núria|||0000-0002-0028-570X
author_facet Gaja Capdevila, Núria|||0000-0002-0028-570X
Hernández, Neus
Yeste, Sandra
Reinoso, Raquel
Burgueño, Javier
Montero, Ana
Merlos, Manuel
Vela, José M.
Herrando-Grabulosa, Mireia|||0000-0002-6685-3220
Navarro, X. (Xavier)|||0000-0001-9849-902X
author_role author
author2 Hernández, Neus
Yeste, Sandra
Reinoso, Raquel
Burgueño, Javier
Montero, Ana
Merlos, Manuel
Vela, José M.
Herrando-Grabulosa, Mireia|||0000-0002-6685-3220
Navarro, X. (Xavier)|||0000-0001-9849-902X
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona. Institut de Neurociències
dc.subject.none.fl_str_mv Amyotrophic lateral sclerosis
Motoneuron degeneration
Sigma-1 receptor
SOD1G93A mice
Spinal nerve injury
topic Amyotrophic lateral sclerosis
Motoneuron degeneration
Sigma-1 receptor
SOD1G93A mice
Spinal nerve injury
description Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that Sig-1R is a target to prevent MN degeneration. In this study, two novel synthesized Sig-1R ligands, coded EST79232 and EST79376, from the same chemical series, with the same scaffold and similar physicochemical properties but opposite functionality on Sig-1R, were evaluated as neuroprotective compounds to prevent MN degeneration. We used an in vitro model of spinal cord organotypic cultures under chronic excitotoxicity and two in vivo models, the spinal nerve injury and the superoxide dismutase 1 (SOD1)G93A mice, to characterize the effects of these Sig-1R ligands on MN survival and modulation of glial reactivity. The antagonist EST79376 preserved MNs in vitro and after spinal nerve injury but was not able to improve MN death in SOD1G93A mice. In contrast, the agonist EST79232 significantly increased MN survival in the three models of MN degeneration evaluated and had a mild beneficial effect on motor function in SOD1G93A mice. In vivo, Sig-1R ligand EST79232 had a more potent effect on preventing MN degeneration than EST79376. These data further support the interest in Sig-1R as a therapeutic target for neurodegeneration.
publishDate 2022
dc.date.none.fl_str_mv 2
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/260278
https://dx.doi.org/urn:doi:10.3390/ijms23126737
url https://ddd.uab.cat/record/260278
https://dx.doi.org/urn:doi:10.3390/ijms23126737
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-096386-B-I00
Ministerio de Sanidad y Consumo CB06/05/1105
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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