title: Role of p75NTR in NMDAR-mediated excitotoxic brain injury in neonatal mice.
abstract: BACKGROUND
  Perinatal brain injury in preterm infants is a major cause of neurological handicap. The role of the neurotrophin receptor p75 (p75(NTR)) in the pathogenesis and repair of neonatal excitotoxic brain injury is unknown. Depending on a complex interplay of neurotrophin signalling, p75(NTR) can, in addition to its trophic function, also induce apoptosis.
  
  
  OBJECTIVE
  We hypothesised that excitotoxicity increases p75(NTR) expression and p75(NTR) knockout (KO) mice have a significantly smaller lesion size upon excitotoxicity as compared to wild-type (WT) mice.
  
  
  METHODS
  We used an established animal model of neonatal excitotoxic brain injury mimicking several key aspects of human preterm brain damage. We subjected five-day-old WT and KO mice to excitotoxic injury by means of a single intracranial ibotenate injection (N-methyl-D-aspartate receptor agonist, NMDAR) into one brain hemisphere. Lesion size, number of activated caspase-3- and apoptosis-inducing factor (AIF)-positive cells were determined as outcome parameters. Gender analyses were taken into account retrospectively.
  
  
  RESULTS
  NMDAR-mediated excitotoxicity induced an upregulation of p75(NTR) expression in the peri-lesion area. Lesion size was significantly increased in female KO as compared to male KO animals. Knockout of p75(NTR) reduced the number of activated caspase-3 but not AIF-positive cells after NMDAR-mediated excitotoxic injury independently of gender.
  
  
  CONCLUSIONS
  Since NMDAR-mediated excitotoxic brain injury induced p75(NTR) expression and caspase-3-activated apoptosis in p75(NTR) KO animals was decreased, we conclude that activation of p75(NTR) contributes to NMDAR-mediated apoptosis in the neonatal brain. An increase in lesion size in female animals after excitotoxic brain injury suggests that in females p75(NTR) seems to play a dual role.
authors.affiliation: Department of Paediatrics IV, Neonatology, Neuropaediatrics and Metabolic Diseases, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Elke.Griesmaier@i-med.ac.at
authors.forename: Elke
authors.initials: E
authors.lastname: Griesmaier
authors.forename: Gerald
authors.initials: G
authors.lastname: Schlager
authors.forename: Karina
authors.initials: K
authors.lastname: Wegleiter
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.forename: Martina
authors.initials: M
authors.lastname: Urbanek
authors.forename: Georg
authors.initials: G
authors.lastname: Simbruner
authors.forename: Matthias
authors.initials: M
authors.lastname: Keller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D020208:Brain Injury, Chronic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009498:Neurotoxins / Q000633:toxicity*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology*
chemical_list: D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse