Cerebral hypoxia-ischemia in the neonate is a major cause of acute mortality and chronic neurologic morbidity in infants and children worldwide, with an incidence of 1-2/1000 live term births. As many as 60% of preterm births can be complicated by hypoxia-ischemia. A significant proportion of the survivors will develop lifelong neurologic handicaps cerebral palsy, epilepsy, and learning disability. Rapid and effective therapeutic intervention is essential to prevent the cascade of events initiated by ischemia that culminate in cell death and ultimate brain damage. Pre-clinical animal models are vital to developing these interventions. The Vannucci lab developed such a model to study hypoxic-ischemic injury to the immature brain. This model was developed in a postnatal day 7 rat, whose brain is roughly equivalent to a 32-36 week gestation human infant, and is now used in research laboratories throughout the world.
Currently, in the laboratory of Newborn Medicine in the Department of Pediatrics, we continue to use this model to address a variety of translational questions. We are currently investigating three interrelated areas of research:
1. The occurrence of hypoxia-ischemia induced seizures in both late gestation preterm and term equivalent newborn rats and the extent to which seizure activity correlates with severity of injury/brain damage. Through the use of video EEG/EMG recordings we can differentiate between clinical seizures, subclinical seizures (abnormal EEG without behavior changes) and behavioral seizures (seizure-like movements with normal EEG). We can further explore this model to test the neuroprotective effects of pharmacologic interventions to prevent HI seizures.
2. The role of mast cells in mediating hypoxic-ischemic injury to the immature brain. Studies from our laboratory have shown that mast cells migrate to the brain during hypoxia-ischemia and are likely the first responders to this insult and the instigators of the inflammatory cascade. Post hypoxic-ischemic mast cell stabilization with the FDA approved drug, chromolyn, provides longterm neuroprotection in the preclinical rat model. Current studies in the laboratory are investigating the window of protection and whether this treatment in synergistic with hypothermia, which is the only approved intervention for HI in current practice. We are also pursuing a line of in vitro research to investigate mechanisms of signaling and cross-talk between brain mast cells and other neural cells.
3. Central to care of asphyxiated newborns are aspects of immediate resuscitation, since such interventions can be both neuroprotective and also deleterious. Our pre-clinical model allows us to specifically address questions such as oxygen, temperature, and drugs during the early resuscitation phase.