Article Text

OXYGEN-INDUCED CASPASE ACTIVATION AND TREATMENT WITH SPECIFIC CASPASE INHIBITORS IN THE IMMATURE RAT BRAIN
  1. M Dzietko1,
  2. C Boerner1,
  3. M Sifringer1,
  4. B Gerstner1,
  5. V Boos1,
  6. E Jacotot2,
  7. D Chauvier2,
  8. M Obladen1,
  9. C Buehrer3,
  10. U FelderhoffMueser1
  1. 1Department of Neonatology, Charite-Universitaetsmedizin Berlin, Berlin, Germany
  2. 2Theraptosis R&D Laboratories, Theraptosis S.A., Romainville, France
  3. 3Department of Neonatology, Basel University Children’s Hospital, Basel, Switzerland

Abstract

Objective Advances in perinatal medicine improved survival of premature infants. However, neurological impairment remains a considerable problem in these children. Clinical studies identified hyperoxia as a risk factor for adverse neurological outcome. Previously, we have shown that short exposure to high oxygen levels can trigger neurodegeneration in the developing rat brain. Toxicity of oxygen is associated with inactivation of intracellular proteins that promote survival and increased expression of the proapoptotic Fas-receptor. Here, we investigated the activation of proapoptotic caspases with or without treatment of a specific caspase-8 inhibitor (TRP801) in a neonatal animal model of hyperoxia-induced brain damage.

Methods 6-day old rat pups were subjected to 80% O2 or room air. TRP801 was co-administered (1 mg/kg, 1% DMSO i.p.) at the beginning of oxygen exposure. Pups were sacrificed after 24 hours and brains were snap frozen for western blot studies of caspase-2, -3 and -8.

Results Immunoblot analysis revealed that hyperoxia increases protein expression of activated caspase-2, -3 and -8. Concomitant application of TRP 801 leads to a downregulation of activated caspases-3 and -8. Caspase-2 expression remains unaffected by this treatment.

Conclusions Caspase-8 inhibition interrupts signalling pathways that lead to apoptotic cell death. These results contribute to explain the neurotoxic effect of oxygen to the immature rat brain and may lead to new neuroprotective strategies.

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