Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 13, Pages -Publisher
MDPI
DOI: 10.3390/ijms22136956
Keywords
sigma-1 receptor; spinal root injury; motoneuron death; endoplasmic reticulum stress
Funding
- Ministerio de Ciencia, Innovacion y Universidades of Spain [RTI2018-096386-B-I00]
- CIBERNED from the Instituto de Salud Carlos III of Spain [CB06/05/1105]
- TERCEL from Instituto de Salud Carlos III of Spain [RD16/0011/0014]
- European Union (ERDF/ESF, Investing in your future)
- AGAUR, Departament d'Empresa i Coneixement de la Generalitat de Catalunya
- European Social Funds
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Research on the neuroprotective role of Sig-1R ligands in a mouse model of spinal root injury showed that they could reduce motor neuron loss by about 20% and modulate endoplasmic reticulum stress markers IRE1 alpha and XBP1, providing a promising target for the treatment of neural injuries.
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 immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate 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 IRE1 alpha 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.
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