Neuroprotective effects of sigma 1 receptor ligands on motoneuron death after spinal root injury in mice

Abstract

Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma‐1 receptor (Sig‐1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig‐1R ligands (PRE‐084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post‐injury (dpi) for immuno-histochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the im-mediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig‐1R ligands PRE‐084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig‐1R specific since they were not produced in Sig‐1R knockout mice. These findings suggest that Sig‐1R is a promising target for the treatment of MN cell death after neural injuries.