EST79232 and EST79376, Two Novel Sigma-1 Receptor Ligands, Exert Neuroprotection on Models of Motoneuron Degeneration

Núria Gaja-Capdevila, Neus Hernández, Sandra Yeste, Raquel F. Reinoso, Javier Burgueño, Ana Montero, Manuel Merlos, José M. Vela, Mireia Herrando-Grabulosa, Xavier Navarro

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Resumen

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
Idioma originalInglés
Número de artículo6737
Número de páginas17
PublicaciónInternational journal of molecular sciences
Volumen23
DOI
EstadoPublicada - 16 jun 2022

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  • CIBERNED_Patología neuromuscular clínica y experimental

    Navarro Acebes, X. (Principal Investigator), Aguilera Avila, J. (Investigador/a), Arbat Plana, A. (Investigador/a), Bosch, A. (Investigador/a), Bruna Escuer, J. (Investigador/a), Candalija Iserte, A. M. (Investigador/a), Casas, C. (Investigador/a), Catala Solsona, J. (Investigador/a), Cobianchi , S. (Investigador/a), Coll Miro, M. (Investigador/a), Cuadras Mas, J. (Investigador/a), Del Valle Macia, J. (Investigador/a), Enriquez Barreto, L. (Investigador/a), Francos Quijorna, I. (Investigador/a), González Pérez, F. J. (Investigador/a), Hernández Martín, J. (Investigador/a), Herrando Grabulosa, M. (Investigador/a), Jaramillo Rodríguez, J. (Investigador/a), Lopez Vales, R. (Investigador/a), López Serrano, C. (Investigador/a), López Álvarez, V. M. (Investigador/a), Martínez Muriana, A. (Investigador/a), Modol Caballero, G. (Investigador/a), Morell Orduña, M. (Investigador/a), Oliva Muñoz, N. D. L. (Investigador/a), Rodriguez Alvarez, J. (Investigador/a), Romeo Guitart, D. (Investigador/a), Santos Rojas, D. H. (Investigador/a), Siedlecki Wullich, D. J. (Investigador/a), Torres Espín, A. (Investigador/a), Udina Bonet, E. (Investigador/a), Garcia Garcia, J. (Investigador/a), Lopez Santos, D. (Investigador/a) & Badia Puiggali, C. (Investigador/a)

    1/01/0831/12/30

    Proyecto: Proyectos y Ayudas de Investigación

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