title: Sigma receptor agonist 2-(4-morpholinethyl)1 phenylcyclohexanecarboxylate (Pre084) increases GDNF and BiP expression and promotes neuroprotection after root avulsion injury.
abstract: Spinal root avulsion leads to a progressive loss of axotomized motoneurons (MNs). Nowadays, there is no effective treatment to prolong MN survival that could permit recovery as a result of delayed surgical repair. Administration of Sigma-1 receptor (Sig-1R) ligands has been reported to promote beneficial effects after several types of neural injury. In order to shed light of whether Sig-1R ligands could promote MN survival after root avulsion, L4-L5 spinal roots were unilaterally avulsed in adult rats and the Sig-1R agonist Pre084 was administered at different doses. The ventral spinal cords of the animals were studied from 3 to 21 days post-operation (DPO) by using histological, immunohistochemical, and Western blot techniques. Daily treatment with 0.25 mg/kg Pre084 significantly promoted MN survival (68% vs 43% in untreated rats) at 21 DPO, an effect that was antagonized by coadministration of BD1063, an antagonist of Sig-1R. There was a reduction in astroglial- associated immunoreactivity in rats treated with Pre084. Moreover, Pre084 produced an increase in the Sig-1R co-chaperone BiP within MNs, and an increase of GDNF expression by astrocytes in the ventral horn early after injury. Although the mechanisms promoting MN survival by Pre084 remain unclear, we hypothesize that it is mediated at least in part through the increase in these cytoprotective factors. Therefore, early application of Sig-1R agonist appears to be a promising therapy to improve MN survival after root avulsion.
authors.affiliation: Group of Neuroplasticity and Regeneration, Institute of Neurosciences, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Penas
authors.forename: Arán
authors.initials: A
authors.lastname: Pascual-Font
authors.forename: Renzo
authors.initials: R
authors.lastname: Mancuso
authors.forename: Joaquim
authors.initials: J
authors.lastname: Forés
authors.forename: Caty
authors.initials: C
authors.lastname: Casas
authors.forename: Xavier
authors.initials: X
authors.lastname: Navarro
mesh_terms: D000818:Animals; D019771:Axotomy; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis*; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D007150:Immunohistochemistry; D009025:Morpholines / Q000494:pharmacology*; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011843:Radiculopathy / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000293:injuries*; D000097605:Sigma-1 Receptor; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D006360:Heat-Shock Proteins; D009025:Morpholines; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate