Anti-inflammatory Intervention and Neurobehavioral Outcome in Neonatal Ischemia (2011 - Present)

Investigator:  Steven Threlkeld, Rhode Island College
Collaborator/Mentor:  Barbara Stonestreet, Women & Infants Hospital

Abstract:  Neonatal cerebral oxygen deprivation and reduced blood flow (hypoxia/ischemia (HI) respectively) can result from umbilical cord occlusion, prolonged labor or preterm birth producing an inflammatory response and neuronal cell death contributing to poor cognitive outcome and learning disabilities later in life. Given limitations of longitudinally monitoring cognitive outcomes in humans following perinatal brain injury, rodent models continue to be utilized to assess potential long-term benefits of translational experimental treatment strategies. Inflamatory mechanisms have been implicated in neuronal and white matter injury following neontal HI and infection, resulting in cognitive delay.  Inter-alpha inhibitor proteins (IAIPs) reduce inflamation in models of adult and newborn sepsis.  IAIPs have beneficial immunomodulatory effects, inhibit destructive proteases secreted by immune cells, and are entering human clinical trials in severe sepsis.  IAIPs and related molecules have been detected in neurons and astrocytes of the brain and have been shown to exhibit neuroprotective effects in an adult rodent stroke model. However, no studies have been performed in neonates.  With the majority of preterm infants exhibiting neurodevelopmental disorders with varying degrees of severity, assessing both the neural benefits and behavioral outcomes of novel treatment strategies are essential for the understanding of pathogenesis and its prevention. The specific aims of this collaborative proposal are: (1) to evaluate the beneficial neuroprotective effects of systemic IAIP administration across three ages (postnatal days 3, 5 and 7) of HI injury in neonatal rats; and (2) to study the long-term domain specific (spatial, non-spatial, working memory, auditory) learning/processing of rats administered IAIPs following neonatal HI.  Using a battery of behavioral tasks ranging in difficulty we will assess the efficacy of IAIPs to prevent neonatal brain damage and subsequent learning impairments in a rat model. Finally, this proposal will enhance collaboration between Rhode Island College and Woman and Infants Hospital of Rhode Island while supporting the novel investigation of neurobehavioral outcome following anti-inflammatory treatment in neonatal HI.