Perinatal Hypoxic-Ischemic Brain Damage: Evolution of an Animal Model

Early research in the Vannucci laboratory prior to 1981 focused largely on brain energy metabolism in the developing rat. At that time, there was no experimental model to study the effects of perinatal hypoxia-ischemia in the rodent, despite the tremendous need to investigate the pathophysiology of perinatal asphyxial brain damage in infants. Accordingly, we developed such a model in the postnatal day 7 rat, using a modification of the Levine preparation in the adult rat. Rat pups underwent unilateral common carotid artery ligation followed by exposure to systemic hypoxia (8% oxygen) at a constant temperature of 37 degrees C. Brain damage, seen histologically, was generally confined to the cerebral hemisphere ipsilateral to the arterial occlusion, and consisted of selective neuronal death or infarction, depending on the duration of the systemic hypoxia. Tissue injury was observed in the cerebral cortex, hippocampus, striatum, and thalamus. Subcortical and periventricular white matter injury was also observed. This model was originally described in the Annals of Neurology in 1981, and during the more than 20 years since that publication numerous investigations utilizing the model have been conducted in our laboratories as well as laboratories around the world. Cerebral blood flow and metabolic correlates have been fully characterized. Physiologic and pharmacologic manipulations have been applied to the model in search of neuroprotective strategies. More recently, molecular biologic alterations during and following the hypoxic-ischemic stress have been ascertained and the model has been adapted to the immature mouse for specific use in genetically altered animals. As predicted in the original article, the model has proven useful for the study of the short- and long-term effects of hypoxic-ischemic brain damage on motor activity, behavior, seizure incidence, and the process of maturation in the brain and other organ systems.