Delayed Postischemic Hypothermia Improves Long-Term Behavioral Outcome after Cerebral Hypoxia-Ischemia in Neonatal Rats

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Abstract
Hypothermia may be an ideal neuroprotective intervention in hypoxic-ischemic encephalopathy after perinatal asphyxia. The present study describes the long-term effects of prolonged resuscitative whole-body hypothermia initiated 2 h after hypoxic-ischemic injury on brain morphology and neuropsychological behavior in 7-d-old rats. After right common carotid artery ligation and exposure to hypoxia of 8% O2 for 105 min, 10 animals were kept normothermic at 37°C and 10 animals were cooled to 30°C rectal temperature for 26 h, starting 2 h after the hypoxic-ischemic insult. All hypoxic-ischemic animals were gavage fed to guarantee long-term survival. Neuroprotection was evaluated by magnetic resonance imaging and behavioral testing. Hypothermia significantly reduced the final size of cerebral infarction by 23% at 6 wk after the insult. The most extended tissue rescue was found in the hippocampus (21%, p = 0.031), followed by the striatum (13%, p = 0.143) and the cortex (11%, p = 0.160). Cooling salvaged spatial memory deficits verified at 5 wk of recovery with Morris Water Maze test; whereas circling abnormalities after apomorphine injection and sensory motor dysfunctions on rotating treadmill improved, yet did not reach statistical significance. When compared with controls, hypoxic-ischemic animals performed worse in all behavioral tests. Hypothermia did not influence functional outcome in controls. Significant correlations between behavioral performance and corresponding regional brain volumes were found. We conclude that 26 h of mild to moderate resuscitative hypothermia leads not only to brain tissue rescue, but most important to long-lasting behavioral improvement throughout brain maturation despite severity of injury and delayed onset of cooling.