Genetic Inhibition of Caspase-2 Reduces Hypoxic-Ischemic and Excitotoxic Neonatal Brain Injury

Carlsson et al. Ann Neurol. 2011 Nov;70(5):781-9. (Impact Factor 8.1)

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.

Ylva Carlsson, MD,1,2 Leslie Schwendimann, BS,3,4 Regina Vontell, MA, HTL (ASCP),5 Catherine I. Rousset, PhD,1,5 Xiaoyang Wang, MD, PhD,1 Sophie Lebon, Ing.,3,4 Christiane Charriaut-Marlangue, PhD,3,4 Veena Supramaniam, MD,6 Henrik Hagberg, MD, PhD,1,2,5 Pierre Gressens, MD, PhD,3,4,5 and Etienne Jacotot, PhD1,3,4,5

From the 1 Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 2 Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden; 3INSERM, U676, Paris, France; 4 Denis Diderot Faculty of Medicine, University Paris Diderot, Sorbonne Paris Cite´ , UMR676, Paris, France; 5 Perinatal Brain Injury Group, Centre for the Developing Brain, Department of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College, London, United Kingdom; and 6Perinatal Imaging Group, Centre for the Developing Brain, Robert Steiner Magnetic Resonance Unit, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, United Kingdom.

ANN NEUROL 2011 Nov;70(5):781-9. © 2011 American Neurological Association