PO-0396 The Sigma-1 Receptor Agonist Pre-084 Protects Against Glutamate Induced Neurotoxicity In Primary Hippocampal Neurons

Abstract

Background Prematurity is a major determinant of neonatal mortality and morbidity. The number of preterm birth is still on the rise. Recently we and others could demonstrate neuroprotective effects of sigma-1 receptor ligands in adult and newborn animal models of brain injury. Since sigma-1 receptor agonists are already undergoing clinical trials in adult neurological disease, they might be considered a promising therapeutic option also in preterm brain injury. We have previously shown that the selective sigma-1 receptor agonist PRE-084 (2-(4-morpholinethyl)1-phenylcyclohexane-carboxylate) protects against neonatal excitotoxic brain injury in vivo . The aim of the present study was to investigate whether PRE-084 is able to prevent neurotoxicity following glutamate exposure in vitro . Methods Cultured primary hippocampal neurons (day in vitro 10) were pre-treated with PRE-084 before glutamate was applied. Subsequently cell death was quantified by means of PI/calcein – AM staining using live confocal microscopy. Neurons were randomly assigned to one of the following groups: i) control, ii) glutamate or iii) glutamate+PRE-084. PRE-084 was applied in two dosages (10 and 100 µM) prior to glutamate. Results The application of PRE-084 significantly reduced the percentage of dead cells (PRE-084 10 µM: 22.09 (20.50;28.84) and 100 µM: 25.87 (18.77;33.40)) compared to the untreated glutamate control group 43.56 (39,86;46.02). Conclusion Our data show that administration of PRE-084 protects against glutamate induced cell death in primary hippocampal neurons. PRE-084 shows considerable promise as a therapeutic strategy in preterm brain injury and might provide an adequate means of combating this major cause of neurological disability in infancy.