Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury

Ylva Carlsson, Leslie Schwendimann, Regina Vontell, Catherine I. Rousset, Xiaoyang Wang, Sophie Lebon, Christiane Charriaut-Marlangue, Veena Supramaniam, Henrik Hagberg, Pierre Gressens, Etienne Jacotot

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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. Interpretation: These data suggest for the first time a role of Casp2 in neonatal brain damage. ANN NEUROL 2011;

Original languageEnglish (US)
Pages (from-to)781-789
Number of pages9
JournalAnnals of neurology
Volume70
Issue number5
DOIs
StatePublished - Nov 2011
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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