EST79232 and EST79376, Two novel sigma-1 receptor ligands, exert neuroprotection on models of motoneuron degeneration
Gaja Capdevila, Núria (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Hernández, Neus (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Yeste, Sandra (Parc Científic de Barcelona)
Reinoso, Raquel (Parc Científic de Barcelona)
Burgueño, Javier (Parc Científic de Barcelona)
Montero, Ana (Parc Científic de Barcelona)
Merlos, Manuel (Parc Científic de Barcelona)
Vela, José M. (Parc Científic de Barcelona)
Herrando-Grabulosa, Mireia (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Navarro, X. (Xavier) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Universitat Autònoma de Barcelona. Institut de Neurociències

Date:	2022
Abstract:	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.
Grants:	Agencia Estatal de Investigación RTI2018-096386-B-I00 Ministerio de Sanidad y Consumo CB06/05/1105
Rights:	Aquest 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.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Amyotrophic lateral sclerosis ; Motoneuron degeneration ; Sigma-1 receptor ; SOD1G93A mice ; Spinal nerve injury
Published in:	International journal of molecular sciences, Vol. 23, Issue 12 (June 2022) , art. 6737, ISSN 1422-0067

DOI: 10.3390/ijms23126737
PMID: 35743175

17 p, 5.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles