title: Delayed application of the haematopoietic growth factors G-CSF/SCF and FL reduces neonatal excitotoxic brain injury.
abstract: BACKGROUND
  Developmental brain injury results in cognitive and motor deficits in the preterm infant. Enhanced glutamate release and subsequent receptor activation are major pathogenetic factors. The effect of haematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF) and flt-3 ligand (FL) on neonatal brain injury is controversially discussed. Timing of treatment is known to be a crucial factor. Based on the hypothesis that an exacerbation of injury is caused by administration of substances in the acute phase, the objective of this study was to evaluate the effect of delayed administration of G-CSF/SCF and FL to protect against excitotoxic brain injury in vivo.
  
  
  METHODS
  In an established neonatal mouse model of excitotoxic brain injury, we evaluated the effect of daily intraperitoneal doses of G-CSF/SCF or FL, starting 60 h after the excitotoxic insult.
  
  
  RESULTS
  Intraperitoneal injections of G-CSF/SCF and FL, given 60 h after the excitotoxic insult, significantly reduced lesion size at postnatal days 10, 18 and 90. G-CSF/SCF treatment resulted in a decrease in apoptotic cell death indicated by reduced caspase-3 activation. G-CSF/SCF and FL treatment did not affect apoptosis-inducing factor-dependent apoptosis or cell proliferation.
  
  
  CONCLUSIONS
  We show that delayed systemic treatment with the haematopoietic growth factors G-CSF/SCF and FL protects against N-methyl-D-aspartate receptor-mediated developmental excitotoxic brain damage. Our results suggest that neuroprotective effects in this neonatal animal model of excitotoxic brain injury depend on the timing of drug administration after the insult.
authors.affiliation: Department of Paediatrics II (Neonatology), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Vera
authors.initials: V
authors.lastname: Neubauer
authors.affiliation: Department of Paediatrics II (Neonatology), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Karina
authors.initials: K
authors.lastname: Wegleiter
authors.affiliation: Department of Paediatrics II (Neonatology), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Posod
authors.affiliation: Department of Paediatrics II (Neonatology), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Urbanek
authors.affiliation: Department of Paediatrics II (Neonatology), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Karina
authors.initials: K
authors.lastname: Wechselberger
authors.affiliation: Department of Paediatrics II (Neonatology), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Kiechl-Kohlendorfer
authors.affiliation: Kinderklinik Dritter Orden, Munich Technical University, Bischof Altmann-Strasse 9, 94032 Passau, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Keller
authors.affiliation: Department of Paediatrics II (Neonatology), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address: Elke.Griesmaier@i-med.ac.at.
authors.forename: Elke
authors.initials: E
authors.lastname: Griesmaier
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018690:Excitatory Amino Acid Agonists; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D007051:Ibotenic Acid; D008565:Membrane Proteins / Q000008:administration & dosage*; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D019089:Stem Cell Factor / Q000008:administration & dosage*
chemical_list: D018690:Excitatory Amino Acid Agonists; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D019089:Stem Cell Factor; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor; D007051:Ibotenic Acid
keywords: Brain injury; Excitotoxic; FL; G-CSF/SCF; Haemotopoietic growth factors; Newborn