Neuroprotective mechanisms of hypothermia have not been clearly established especially in the immature brain. To investigate the effect of hypothermia on cell death and cell survival signal pathways, we studied caspase-3-like activity and activation of Akt in a rat model of neonatal hypoxic-ischemic (H-I) brain injury. Seven-day-old rats underwent a combination of left common carotid artery ligation and exposure to 8% O(2) for 1-h (n=32). During recovery, the body temperature was reduced to 30 degrees C for 24 h in 16 animals, but was kept at 37 degrees C in 16 animals. Post-ischemic hypothermia was shown to diminish the caspase-3-like activity compared to normothermia at 6 and 24 h after H-I. Phospho-Akt was increased during the early reperfusion period after H-I in the normothermia group, but hypothermia rather decreased this enhanced phosphorylation of Akt following H-I. These results indicated that hypothermia may have some depressant effects on both cell death and cell survival signal pathways, and that Akt conceivably may not play a major role in the neuroprotective effect of hypothermia in the immature brain.