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1083 The Highly Selective Sigma-1 Receptor Agonist Pre-084 Reduces Inflammation-Sensitized Hyperoxia-Induced Injury in the Developing Rat Brain
  1. A Posod1,
  2. Y Krepp1,
  3. V Neubauer1,
  4. K Wegleiter1,
  5. M Urbanek1,
  6. M Keller1,2,
  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

Background Supraphysiologic oxygen concentrations are toxic to the developing brain. Inflammatory processes increase the risk of brain injury. We have previously shown a protective effect of dextromethorphan, a NMDA receptor antagonist and sigma-1 receptor (σ1R) agonist, in an animal model of hyperoxia-induced neonatal brain injury. In adult brain injury, sigma agonists have a proven therapeutic potential.

Aim To assess the highly selective σ1R agonist PRE-084 in a newborn animal model of inflammation-sensitized hyperoxia-induced brain injury.

Methods Rat pups were randomly pre-sensitized with a single intraperitoneal (ip) injection of i) LPS or ii) vehicle on postnatal day 3. On postnatal day 5, pups were ip-injected with i) PRE-084 1µg/g bodyweight or ii) vehicle and were subsequently subjected to either i) hyperoxia (HX, FiO2>0.9) or ii) normoxia (NX, FiO2=0.21) for 24 hours. At the end of exposure, animals were sacrificed and brains were processed for caspase-3 analysis using immunohistochemistry and Western Blotting.

Results A single LPS injection significantly increased the number of activated caspase-3-positive cells in cortical grey matter after hyperoxic exposure, which was reduced by PRE-084 administration (mean number of cells ±SEM; LPS_NX_vehicle 31.26±1.29 vs. LPS_HX_vehicle 38.11±1.13, p<0.01 vs. LPS_HX_PRE-084 33.66±1.54, p<0.05; n=6–7). Western Blot analyses showed a strong reduction in caspase-3 cleavage in PRE-084-treated pups compared to vehicle-injected controls in both pre-sensitized and non-pre-sensitized animals after hyperoxic exposure.

Conclusion PRE-084 reduces inflammation-sensitized hyperoxia-induced injury in the developing rat brain by inhibition of apoptosis. Sigma agonists are a potential therapeutic approach in perinatal brain injury and merit further studies.

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