title: Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury.
abstract: OBJECTIVE
  Perinatal brain injury is a major cause of neurodevelopmental handicaps. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to cell damage and death, including caspase-dependent apoptosis. Caspase-2 (Casp2; Nedd-2, Ich-1) is a developmentally regulated initiator caspase, which poorly cleaves other caspases but can initiate mitochondrial outer membrane permeabilization. We have investigated if Casp2 could mediate perinatal ischemic brain damage.
  
  
  METHODS
  Casp2 expression in human neonatal brains and developmental patterns in rats and mice were evaluated. Casp2-deficient (Casp2(-/-)), wild-type (WT), and heterozygous (Casp2(+/-)) newborn C57BL/6 mice were subjected to hypoxia-ischemia (unilateral carotid occlusion + exposure to 10% oxygen for 50 minutes) or intracerebral injection of the excitotoxic N-methyl-D-aspartate-receptor agonist ibotenate. In addition, Casp2 specific siRNAs were preinjected into the brain of WT newborn mice 24 hours before ibotenate treatment. Brain tissues were examined by immunohistochemical staining (cresyl violet, MAP2, NF68, Casp2, Casp3) and Western blotting. Lesion volumes and injury in the cortical plates and white matter were quantified together with activated Casp3.
  
  
  RESULTS
  Casp2 is highly expressed in the neonatal brain. Casp2-deficient mice subjected to hypoxia-ischemia at postnatal day 9 present significantly lower cerebral infarction, reduced white matter injury, and reduced Casp3 activation in the thalamus and hippocampus. Both Casp2(-/-) mice and siRNA-administered WT mice conferred reduction of gray and white matter injury after excitotoxic insult at postnatal day 5. Casp3 activation was also found reduced in Casp2-deficient mice subjected to excitotoxicity.
  
  
  CONCLUSIONS
  These data suggest for the first time a role of Casp2 in neonatal brain damage.
authors.affiliation: Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ylva
authors.initials: Y
authors.lastname: Carlsson
authors.forename: Leslie
authors.initials: L
authors.lastname: Schwendimann
authors.forename: Regina
authors.initials: R
authors.lastname: Vontell
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Rousset
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wang
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebon
authors.forename: Christiane
authors.initials: C
authors.lastname: Charriaut-Marlangue
authors.forename: Veena
authors.initials: V
authors.lastname: Supramaniam
authors.forename: Henrik
authors.initials: H
authors.lastname: Hagberg
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.forename: Etienne
authors.initials: E
authors.lastname: Jacotot
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D053143:Caspase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002544:Cerebral Infarction / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007051:Ibotenic Acid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009498:Neurotoxins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists
chemical_list: D009498:Neurotoxins; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D007051:Ibotenic Acid; D053143:Caspase 2