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299 PRE-084, A Sigma-1 Receptor Ligand, Protects Against Excitotoxic Perinatal Brain Injury in Newborn Mice
  1. E Griesmaier1,
  2. A Posod1,
  3. MJ Gross1,
  4. V Neubauer1,
  5. K Wegleiter1,
  6. M Hermann2,
  7. M Urbanek1,
  8. M Keller1,3,
  9. U KiechlKohlendorfer1
  1. 1Department of Paediatrics IV, Division of Neonatology
  2. 2Department of Anaesthesiology, Innsbruck Medical University, Innsbruck, Austria
  3. 3Department of Paediatrics, Children’s Hospital Passau, Passau, Germany

Abstract

Background Excessive glutamate release followed by N-methyl-D-aspartate receptor (NMDAR) activation displays an important cascade in the pathophysiology of perinatal brain injury. We have previously shown that dextromethorphan, a low-affinity NMDAR antagonist, is neuroprotective in an animal model of neonatal excitotoxic brain injury. Of interest, dextromethorphan also shows agonistic properties at the sigma-1 receptor (σ1R). Sigma-1 agonists have given beneficial results in animal models of adult brain injury.

Aim of the study To evaluate the effect of the selective σ1R agonist 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE-084) in neonatal excitotoxic brain injury.

Results A single intraperitoneal injection of 0.1 µg/g (low dose) or 10 µg/g (high dose) bodyweight (bw) PRE-084, given 1 h after the excitotoxic insult, significantly reduced lesion size in cortical gray matter 24 h and 120 h after the insult. Repetitive injections of 0.1 µg/g PRE-084 proved to be equally effective. PRE-084 treatment resulted in a decrease in cell death indicated by reduced TUNEL positivity and caspase-3 activation. PRE-084 reduced the number of isolectin B4-positive, activated microglial cells. Quantitative real-time PCR analysis showed no effect on σ1R gene expression at 1, 4, 8, 12, 24 and 48 h after intracranial ibotenate injection compared to healthy controls. In vitro PRE-084 protected against glutamate-induced morphological and functional changes in primary hippocampal neurons.

Conclusion We demonstrate that systemic treatment with the highly selective σ1R agonist PRE-084 protects against NMDAR-mediated excitotoxic brain damage.

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