title: The effect of postischemic hypothermia on apoptotic cell death in the neonatal rat brain.
abstract: OBJECTIVE
  Hypothermia is the most effective neuroprotective therapy against ischemic injury in the developing brain. However, the mechanism of hypothermic neuroprotection is not well understood. We sought to investigate whether hypothermia mediates neuroprotection by modulating ischemia-induced apoptosis.
  
  
  METHODS
  Seven-day-old rat pups were randomly assigned to either control or hypoxia-ischemia (HI) groups. In the HI group, the internal carotid artery was ligated and cut. This was followed by transient hypoxia at 8% oxygen for 90 min. In the control rats, the internal carotid was isolated but not ligated. Immediately after the hypoxic episode, pups in the HI group were either placed in water baths maintained at 28°C for 24 h (core temperatures at 31°C) or they remained in a normothermic environment. Animals were sacrificed at 24, 48 and 72 h and 1 week after the HI insult. Brain sections were processed for immunohistochemistry and Western blots.
  
  
  RESULTS
  Caspase 3 expression was significantly higher in the core compared with the peri-infarct area at all time points in normothermic rats. Hypothermia reduced caspase 3 expression in the core but had little effect in the peri-infarct area. Hypothermia reduced apoptosis-inducing factor translocation to the nucleus in the core and peri-infarct area. Concurrently, X-linked inhibitor of apoptosis (XIAP) expression was significantly potentiated in the hypothermic-ischemic core but not in the peri-infarct area.
  
  
  CONCLUSIONS
  Hypothermic modulation of caspase-dependent apoptosis may be mediated by upregulating XIAP. However, the effect of hypothermia on caspase-independent apoptosis may be mediated by XIAP-independent mechanisms. Importantly, these effects are mediated in both the core and the penumbral regions of ischemic lesion.
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada. rand.askalan@sickkids.ca
authors.forename: Rand
authors.initials: R
authors.lastname: Askalan
authors.forename: Carol
authors.initials: C
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.forename: Edward
authors.initials: E
authors.lastname: Armstrong
authors.forename: Jerome Y
authors.initials: JY
authors.lastname: Yager
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3