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9 The Sigma-1 Receptor Agonist PRE-084 Attenuates Inflammation-Sensitized Nmdar-Mediated Excitotoxic Brain Injury in Newborn Mice
  1. A Posod1,
  2. K Neumayer1,
  3. V Neubauer1,
  4. M Keller1,2,
  5. K Wegleiter1,
  6. M Urbanek1,
  7. U Kiechl-Kohlendorfer1,
  8. E Griesmaier1
  1. 1Department of Paediatrics IV, Division of Neonatology, Innsbruck Medical University, Innsbruck, Austria
  2. 2Department of Paediatrics, Children’s Hospital Passau, Passau, Germany

Abstract

Excitotoxicity and inflammation play crucial roles in the etiopathogenesis of perinatal brain injury. We have shown that the sigma-1 receptor agonist 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE-084) protects against N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxic brain injury. In models of adult central nervous system pathology, PRE-084 has demonstrated potent anti-inflammatory properties, which makes it a promising candidate for countering inflammation-enhanced perinatal brain injury.

In the present study we evaluated the effect of PRE-084 in a neonatal mouse model of inflammation-sensitized excitotoxic brain injury.

From postnatal days 1 to 4, pups were pre-sensitized by intraperitoneal injections of IL-1beta (10ng). Two hours after the last IL-1beta dose, pups received an intracranial ibotenate injection, 1 hour after the insult they were randomly treated with i) 0.1 µg/g bodyweight PRE-084 or ii) vehicle.

Administration of PRE-084 resulted in a significant decrease in cortical grey (mean length of the lesion: vehicle 780.00µm ± 495.35 vs. PRE-084 433.33µm±116.51; n=8–9; p<0.05) and adjacent white matter damage (mean length of the lesion: vehicle 767.50µm ± 489.07 vs. PRE-084 391.11µm±126.14; n=8–9; p<0.05). No sex-specific differences in lesion size were detected (n=3–6, p>0.05). PRE-084 treatment significantly reduced the number of isolectin B4-positive activated microglial cells in perilesional white matter (mean number of isolectin B4-positive activated microglia vehicle 36.40±6.96 vs. PRE-084 19.93±11.99; n=5; p<0.05).

We are the first to report that PRE-084 reduces inflammation-sensitized NMDAR-mediated excitotoxic perinatal brain damage. Since sigma-1 receptor agonists are investigated in clinical trials in adult neurological diseases, they might be considered a promising therapeutic option also in perinatal brain injury.

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