Mechanisms of Injury and Neuroprotective Strategies for Treatment of Inflammation-Related Preterm Brain Injury

Abstract

Postnatal infection is an ongoing issue in neonatal intensive care units, disproportionately affecting preterm born infants. Accordingly, exposure to severe infection and the resulting inflammatory response is associated with persistent disturbances in brain development and neurobehavioral outcomes. However, a causative role for less severe but prolonged postnatal infection and inflammation in these deficits, and the underlying cellular mechanisms, remain elusive. Further, at present there are no effect treatments to improve neurological outcomes in these infants. First, my research showed that exposure to postnatal systemic inflammation induced long-term microstructural alterations to the brain involving impairments in oligodendrocyte maturation and axonal myelination in the white matter, and in neuronal dendritic development in the cerebral cortex. These deficits could be detected using advanced image techniques, and functionally manifested as impaired motor coordination and cognition. Second, my research showed that disturbances in central IGF receptor signalling may contribute to this diffuse pattern of brain injury following postnatal systemic inflammation, and that treatments targeted towards promoting IGF receptor signalling were neuroprotective. Finally, my research showed that directly targeting the immune response to treat inflammation-related preterm brain injury may not be a clinically translatable intervention due to the adverse systemic side effects. Together, these studies further our understanding of the mechanisms of preterm brain injury, its detection, and potential treatments.