Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1 G93A ALS Mice
Gaja Capdevila, Núria (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)
Herrando-Grabulosa, Mireia (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)

Data:	2021
Resum:	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.
Ajuts:	Agencia Estatal de Investigación RTI2018-096386-B-I00 Ministerio de Sanidad y Consumo CB06/05/1105 Ministerio de Economía y Competitividad RD16/0011/0014
Drets:	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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Sigma-1 receptor ; Amyotrophic lateral sclerosis ; Motoneuron ; SOD1 G93A transgenic ; Neurodegenerative disease
Publicat a:	Frontiers in Pharmacology, Vol. 12 (december 2021) , ISSN 1663-9812

DOI: 10.3389/fphar.2021.780588
PMID: 34955848

13 p, 5.7 MB

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