Sex differences in brain injury following pediatric cardiac arrest

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DESCRIPTION (provided by applicant): Pediatric cardiac arrest is a common and devastating condition which remains poorly understood. Mortality rates are extremely high and brain injury is the most common cause of death. The majority of research regarding cardiac arrest over the past 50 years has focused on improving rates of return of spontaneous circulation (ROSC), with significant progress leading to increased survival rates. However, without interventions to minimize organ injury, there is an increase in long-term health issues associated with our improved resuscitation practices. This has been termed the post-cardiac arrest syndrome, consisting predominantly of long-term neurological deficits. Indeed, several interventions that have been useful in improving ROSC, have not shown benefit in improving long term outcome. There have been numerous pre- clinical translational studies of cardiac arrest in adult animals demonstrating various pharmacological interventions to improve neuronal survival following global cerebral ischemia. However, to date, there are very few studies in pediatric cardiac arrest, as models are scarce. In the current proposal, we describe the first pediatric cardiac arrest model utilizing mice to study the effects of cardiac arrest on neuronal survival and test new therapies. Epidemiologic studies in adults have suggested that females have better outcomes after CA when compared to males. Numerous experimental studies in adult animal models have recapitulated this clinical data, showing that female animals exhibit significantly less brain injury following cerebral ischemia than males. The sex difference observed in experimental adult animals can be nearly completely explained by the high levels of estrogen in female animals, as removal of endogenous sex steroids (ovariectomy) increases female brain injury to male levels and estrogen replacement returns female injury to intact animal levels. Not surprisingly, we did not observe a gender difference in ischemic injury in pediatric mice, consistent with pre- pubertal state of low estrogen in both male and female animals. Interestingly, when estrogen is exogenously administered we observe a remarkable sex-difference in response to estrogen neuroprotection. We observed that a single intravenous estrogen dose administered at a clinically relevant time point following CA/CPR (30 min) provides protection to the female brain, while having no effect in the male brain. Therefore, the aims of the current proposal are designed to further characterize our novel pediatric cardiac arrest model and begin to elucidate the molecular mechanisms of sexually dimorphic estrogen neuroprotection observed at this developmental stage. Therefore, we will 1) establish the role of estrogen in determining neuronal injury following pediatric cardiac arrest and 2) determine the relative contribution of estrogen receptors alpha and beta (ERα and ERß) in estrogen neuroprotection. 3) Finally, determine the molecular mechanism of estrogen neuroprotection in pediatric cardiac arrest.