Negative Impact of Sigma-1 Receptor Agonist Treatment on Tissue Integrity and Motor Function Following Spinal Cord Injury.

Alise Lattard,Gaëtan Poulen,Florence E Perrin,Sylvain Bartolami,Yannick N Gerber

doi:10.3389/fphar.2021.614949

Abstract

In traumatic spinal cord injury, the initial trauma is followed by a cascade of impairments, including excitotoxicity and calcium overload, which ultimately induces secondary damages. The sigma-1 receptor is widely expressed in the central nervous system and is acknowledged to play a key role in calcium homeostasis. Treatments with agonists of the sigma-1 receptor induce beneficial effects in several animal models of neurological diseases. In traumatic injury the use of an antagonist of the sigma-1 receptor reversed several symptoms of central neuropathic pain. Here, we investigated whether sigma-1 receptor activation with PRE-084 is beneficial or detrimental following SCI in mice. First, we report that PRE-084 treatment after injury does not improve motor function recovery. Second, using ex vivo diffusion weighted magnetic resonance imaging completed by histological analysis, we highlight that σ1R agonist treatment after SCI does not limit lesion size. Finally, PRE-084 treatment following SCI decreases NeuN expression and increases astrocytic reactivity. Our findings suggest that activation of sigma-1 receptor after traumatic spinal cord injury is detrimental on tissue preservation and motor function recovery in mice.

Highlights

Traumatic spinal cord injury (SCI) results in 0.6–0.9 million annual new cases worldwide (Kumar et al, 2018)
Σ1R is expressed in neurons, astrocytes, oligodendrocytes and microglia and is found at the endoplasmic reticulum (ER) membrane that is associated with the mitochondria (Mitochondria-Associated ER Membranes [MAMs]) [for review see (Penke et al, 2018)]. σ1R, that forms a complex at MAMs with BiP
The regularity index that reflects the number of normal step sequence patterns relative to the total number of paw placements (Figure 1C) and the base of support of the hind paws were not improved in injured mice treated with PRE-084

Summary

INTRODUCTION

Traumatic spinal cord injury (SCI) results in 0.6–0.9 million annual new cases worldwide (Kumar et al, 2018). Following the primary traumatic mechanical disruption of spinal cord tissues, a cascade of events including vascular impairment, mitochondrial dysfunction, excitotoxicity and calcium overload characterizes the secondary phase of injury and further exacerbates the lesion. PRE-084 and Spine Cord Injury (binding immunoglobulin protein), another chaperone protein, is a Ca2+ sensitive and ligand-operated receptor chaperone at MAMs (Hayashi and Su, 2007). Using excitotoxic injury in organotypic spinal cord slices, Guzmán-Lenis et al demonstrated that PRE-084 induces a neuroprotective effect and decreases neuronal damage and enhances axonal re-growth (Guzman-Lenis et al, 2009). It is of interest to investigate the role of σ1R activation on motor function recovery following SCI. We assessed the effect of PRE-084 treatment following lateral hemisection of the mouse spinal cord on motor recovery and spinal cord structure at tissue and cellular levels

MATERIAL AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT