Brain damage in the Levine preparation (unilateral common carotid artery ligation with hypoxia) consists of ischemic neuronal alterations in the ipsilateral forebrain. As the model has been restricted to adult animals, unilateral common carotid artery ligation was carried out in 7-day-postnatal rats. Four to 8 hours later the 25 pups were exposed to 8% oxygen at 37 degrees C for 3.5 hours. Controls consisted of littermates subjected to carotid ligation without subsequent hypoxia, hypoxia without prior ligation, and neither ligation nor hypoxia. After hypoxia the animals were returned to their dams and appeared normal for up to 50 hours. All pups were then killed by perfusion-fixation. Moderate to severe ischemic neuronal changes were seen in the ipsilateral cerebral cortex, striatum, and hippocampus in at least 90% of the animals and included infarction in 56% of the brains. Cortical damage was occasionally laminar but more often occurred in columns at right angles to the pial surface. Unlike adult animals, there was necrosis of white matter, greater ipsilaterally, originating in and spreading from myelinogenic foci. The evolution of ischemic cell change and the associated gliomesodermal reaction was more rapid than in the adult. In 22 additional pups subjected to carotid artery ligation and hypoxia, brains were analyzed for water content. Significant increases (0.6 to 3.3%) in water content of the ipsilateral hemispheres occurred in 11 of 22 brains (50%). Unilateral ischemia combined with hypoxia in developing rats therefore results in neuronal destruction in the same brain regions as in adult animals, but also causes necrosis of white matter. The incidence of increased water content was similar to that of overt infarction. Thus, as previously shown in the adult, brain edema is a consequence rather than a cause of major ischemic damage in the immature animal.

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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°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.

ABSTRACT. Cerebral hypoxia-ischemia remains a major cause of acute perinatal brain injury, leading ultimately to neurologic dysfunction manifest as cerebral palsy, mental retardation, and epilepsy. Research in experimental animals over the past 10 or more years has expanded greatly our understanding of the cellular and molecular events that occur during a hypoxic-ischemic insult to brain, and recent discoveries have suggested that metabolic pertubations arising in the recovery period after resuscitation contribute substantially to the nature and extent of neuronal destruction. The review focuses on those neurochemical processes responsible for the maintenance of cellular homeostasis and how these mechanisms fail in hypoxia-ischemia to culminate in brain damage. Knowledge of these critical events has opened new avenues of potential therapy for the fetus and newborn infant subjected to cerebral hypoxiaischemia to prevent the serious delayed effects of perinatal brain injury. Perinatal cerebral hypoxia-ischemia typically is initiated by compromised placental or pulmonary gas exchange which leads to systemic hypoxia/anoxia with or without concurrent hypercapnia (asphyxia) (1). Hypoxia/hypercapnia increases CBF adequate to maintain brain metabolism stable until cerebral ischemia supervenes owing to cardiac depression with secondary bradycardia and systemic hypotension. With the neuronal oxygen and glucose debt arising from ischemia, oxidative metaboReceived August 16, 1989; accepted November 30, 1989. Supported by Grants HD-09 109, HD-15738, HD-199 13, and HL-19190 from the NIH and by grants from the American Heart Association and American Diabetes Association. lism shifts to anaerobic glycolysis with its inefficient generation of high-energy phosphate reserves necessary to maintain cellular ionic gradients and other metabolic processes. Ultimately, cellular energy failure occurs, which, if not promptly reversed, results in death of the cell.Over the past decade, a wealth of research has expanded our knowledge of those critical cellular metabolic events that eventually lead to tissue injury arising from hypoxia-ischemia. Investigations have shown that hypoxia-ischemia sets in motion a cascade of biochemical alterations that are initiated during the course of the insult and that proceed well into the recovery period after resuscitation. This review will highlight those cellular processes involved in this metabolic cascade and how they evolve into perinatal hypoxic-ischemic brain damage. CELLULAR ENERGY TRANSFORMATIONSATP is the primary energy modulator of the cell (2-4). Its two -P exist at an energy level capable of providing the necessary driving force for innumerable biochemical reactions and physiologic processes. ATP not only promotes energy consuming reactions but also drives physiologic processes (e.g. ion pumping) by acid hydrolysis. As such, the compound provides the cellular free energy necessary to maintain neuronal viability with its specialized function.Under physiologic conditions, cellular ATP is maint...

Cerebral hypoxia-ischemia (asphyxia) occurring in the fetus and newborn infant is a major cause of acute mortality and chronic neurological disability in survivors. This review highlights many practical aspects of perinatal hypoxic-ischemic brain damage, including neuropathological features, obstetrical antecedents, and clinically important aspects of identification, management, and prognosis. Diagnostic techniques, including neuro-imaging, to diagnose hypoxic-ischemic encephalopathy also are discussed. A thorough knowledge of the clinical spectrum of perinatal hypoxic-ischemic encephalopathy should enable neonatologists to undertake appropriate management strategies and prognostic indicators.

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In conclusion, our immature rat model has gained wide acceptance as the animal model of choice to study basic physiologic, biochemical, and molecular mechanisms of perinatal hypoxic-ischemic brain damage. In addition, the model has been used extensively to study those physiologic and therapeutic variables which either are deleterious or beneficial to the perinatal brain undergoing hypoxia-ischemia. As therapeutic interventions are tested in the animal setting, the results will provide important information regarding the effect of these agents in the human setting.

Abstract— The ability of rats of different ages to survive exposure to anoxia was correlated with rates of high energy phosphate consumption (metabolic rates) of the fore‐brain. Fetal rats at term, delivered by hysterotomy following maternal decapitation, survived in nitrogen at 37°C twice as long as 1‐day‐old neo‐nates, 5 times longer than 7‐day‐old rats, and 45 times longer than adults. During ischemia induced by decapitation, the cerebral concentrations of the labile energy reserves (ATP, ADP, P‐creatine, glucose and glycogen) and of lactate were determined in fetuses, 1‐ and 7‐day post‐natal animals. From the changes, the cerebral energy use rates were calculated to be 1·57 mmol/kg/min in fetuses, 1·33 mmol/kg/min in 1‐day‐olds and 2·58 mmol/kg/min in 7‐day‐olds. Maximal rates of lactate accumulation during ischemia, as a measure of glycolytic capacity, were comparable in fetuses and neonates, but were about twice as great in 7‐day‐old rats. It is concluded that in post‐natal animals survival in anoxia and cerebral energy consumption are inversely, and nearly quantitatively, related. However, the reduced cerebral energy requirement cannot entirely account for the greater anoxic resistance of fetuses.