Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1G93A ALS Mice.

Núria Gaja-Capdevila,Xavier Navarro,Neus Hernández,Mireia Herrando-Grabulosa

doi:10.3389/fphar.2021.780588

Abstract

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 SOD1G93A 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 SOD1G93A 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 SOD1G93A mice. In conclusion, Sig-1R ligands are promising tools for ALS treatment, although more research is needed to ascertain their mechanisms of action.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of upper and lower motoneurons (MNs), causing muscle paralysis and early death
The results of this study demonstrate the beneficial effects of the Sigma-1 receptor (Sig-1R) agonist PRE-084 as well as the Sig-1R antagonist BD1063, on preserving neuromuscular function and attenuating MNs loss in the SOD1G93A mouse model of ALS
Whereas previous studies have reported that PRE-084 (Mancuso et al, 2012) and SA4503 (Ono et al, 2014) treatment ameliorated the progression and survival of spinal MNs, we report for the first time that a Sig-1R antagonist, such as BD1063, has neuroprotective effects in preclinical models of ALS

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of upper and lower motoneurons (MNs), causing muscle paralysis and early death. The generation of transgenic animal models carrying ALS-related mutations has accelerated the research on physiopathology and preclinical therapeutic assays for ALS. Since the first mutation identified in familiar ALS was in the SOD1 gene (Rosen et al, 1993), the SOD1G93A mouse is the most widely used ALS model, which develops the main clinical, electrophysiological and histopathological features of both familial and sporadic forms of the disease (Turner and Talbot, 2008; Mancuso et al, 2011b). Despite mutations in SOD1 gene are present in 20% of familiar ALS cases and only 2% of all ALS cases (Ragagnin et al, 2019), the interest of the SOD1 transgenic models is increased because alterations in SOD1 protein occur in sporadic ALS cases (Bosco and Landers, 2010), and accumulation of wild-type SOD1 causes ALS (Graffmo et al, 2013)

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