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

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 hypoxicischemic injury on brain morphology and neuropsychological behavior in 7-d-old rats. After right common carotid artery ligation and exposure to hypoxia of 8% O 2 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 ϭ 0.031), followed by the striatum (13%, p ϭ 0.143) and the cortex (11%, p ϭ 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, hypoxicischemic 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. (1), a profound, hypoxic-ischemic insult in the human fetus and newborn with a high rate of permanent neuropsychological damage and mortality. A severe acute insult may predominantly affect the thalami, the basal ganglia, the hippocampus, and the brain stem with relative preservation of the cerebral cortex and the subcortical white matter (2). After birth, the clinical signs of perinatal asphyxia include neurologic abnormalities such as coma, seizures, or hypotonia, combined with cardiopulmonary compromise. The newly born infant often requires resuscitation and rapid transfer to the tertiary center for injury severity evaluation and neurologic intensive care. Such support could include specific interventions for hypoxic-ischemic encephalopathy 1 or 2 h into the reperfusion phase from cerebral HI. Despite the fact that perinatal asphyxia closely corresponds to experimental models of cerebral HI, where successful neuroprotective interventions were introduced, presently no agent has been proven useful to ameliorate the chronic handicapping conditions of perinatal asphyxia in the clinical setting (3).In the present clinical situation, neuroprotection can at best be initiated hours after perinatal asphyxia. Such a postischemic or resuscitative neuroprotective measure is hypot...

The Cannabinoid Agonist Win55212 Reduces Brain Damage in an In Vivo Model of Hypoxic-Ischemic Encephalopathy in Newborn Rats

“…Some of these reports have described a reduction by 42%-65% of the injured area when using hypothermia as neuroprotective strategy (30,31), a proportion very similar to that obtained with WIN. In addition, WIN reduced the shrinkage of the ipsilateral hemisphere observed after HI.…”

Long-Term Neuroprotective Effect of Postischemic Hypothermia in a Neonatal Rat Model of Severe Hypoxic Ischemic Encephalopathy: A Comparative Study on the Duration and Depth of Hypothermia

“…By using a flexible temperature probe, rectal temperature was measured at 1 and 4 h, and thereafter every 4 h until the end of each intervention period. Through the period of temperature intervention, pups were fed five times per day with 0.4 mL of commercially available ready-to-feed formula by using 22G-animal feeding needle with round (15). After temperature intervention, the pups were returned to their dams until the end of imaging studies and functional studies at 5 wk postinsult.…”

“…The 7-d-old rat with unilateral carotid artery ligation and subsequent exposure to 8% hypoxia is the most commonly used model to evaluate the efficacy of therapeutic interventions in the developing brain (12), and several studies have used this Rice-Vannucci model (RVM) to test the effects of HT (10,11,(13)(14)(15)(16)(17)(18)(19). However, an experimental design composed of a shorter duration of hypoxia, representing "mild" ischemic lesions, is not appropriate for evaluating the neuroprotective effect of HT against severe HIE.…”

Late Measures of Brain Injury After Neonatal Hypoxia–Ischemia in Mice

“…After hypoxic exposure, pups that have formed an experimental group were returned to their dams. Because it has been shown that carotid artery ligation without hypoxia (sham) produced neither brain damage 9 nor functional impairments in rodents, 10,11 control animals consisted of age-and strain-matched naïve (no HI) mice.…”