Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic-ischemic brain injury.
BACKGROUND
[corrected] Hypoxia-ischemia (HI) injury in term infants develops with a delay during the recovery phase, opening up a therapeutic window after the insult. Hypothermia is currently an established neuroprotective treatment in newborns with neonatal encephalopathy (NE), saving one in nine infants from developing neurological deficits. Caspase-2 is an initiator caspase, a key enzyme in the route to destruction and, therefore, theoretically a potential target for a pharmaceutical strategy to prevent HI brain damage.


METHODS
The aim of this study was to explore the neuroprotective efficacy of hypothermia in combination with caspase-2 gene deficiency using the neonatal Rice-Vannucci model of HI injury in mice.


RESULTS
HI brain injury was moderately reduced in caspase-2(-/-) mice as compared with wild-type (WT) mice. Five hours of hypothermia (33 °C ) vs. normothermia (36 °C) directly after HI provided additive protection overall (temperature P = 0.0004, caspase-2 genotype P = 0.0029), in the hippocampus and thalamus, but not in other gray matter regions or white matter. Delayed hypothermia initiated 2 h after HI in combination with caspase-2 gene deficiency reduced injury in the hippocampus, but not in other brain areas.


CONCLUSIONS
In conclusion, caspase-2 gene deficiency combined with hypothermia provided enhanced neuroprotection as compared with hypothermia alone.
Department of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. ylva.carlsson@vgregion.se
Ylva
Y
Carlsson
Xiaoyang
X
Wang
Leslie
L
Schwendimann
Catherine I
CI
Rousset
Etienne
E
Jacotot
Pierre
P
Gressens
Marianne
M
Thoresen
Carina
C
Mallard
Henrik
H
Hagberg
D000818:Animals; D000831:Animals, Newborn; D053143:Caspase 2 / Q000235:genetics*; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout
D053143:Caspase 2