Preterm brain injury: mechanisms and neuroprotective treatments

Abstract

This thesis explored two neuroprotective treatments (human recombinant erythropoietin (rEPO) and sympathetic nervous system (SNS) inhibition) for hypoxic-ischemic (HI) preterm brain injury, and characterised the neural injury associated with fetal exposure to gram-positive bacteria, which is currently poorly understood. Examining the neuroprotective efficacy of delayed treatment with high-dose rEPO was the primary focus of my thesis. My studies showed that the time of treatment initiation is critical for neuroprotection with rEPO, as delayed treatment starting at the end of latent phase (6 hours after severe HI) was not neuroprotective. Furthermore, delayed treatment with repeated bolus injections of rEPO given every 48 hours (comparable to the treatment regimen in the ongoing trials in preterm infants) exacerbated neural injury. These data strongly suggest the need for further preclinical testing of rEPO in multiple experimental paradigms. The second set of studies examined if SNS inhibition after HI would attenuate delayed cerebral hypoperfusion and associated hypoxia to improve neural outcomes. My studies showed that SNS inhibition increased cerebral blood flow, confirming that delayed cerebral hypoperfusion after HI is mediated by SNS activation. However, SNS inhibition also increased abnormal epileptiform activity after HI, which increased cerebral oxygen demand. Despite increased cerebral perfusion, oxygen delivery was not sufficient to meet this increased metabolic demand leading to a greater mismatch between cerebral metabolism and perfusion, and exacerbation of neural injury. These data underscore the importance of regulation of neural activity and cerebral perfusion after HI to achieve neuroprotection. Additionally, these studies showed that SNS activation during post-HI seizures restricted cerebral blood flow, but this did not impair cerebral oxygenation; suggesting that infrequent post-HI seizures of short-duration do not pose a metabolic challenge in the preterm brain. Finally, I examined the neural effects of fetal exposure to inflammation induced with the gram-positive bacterial product, Picibanil. Systemic exposure to Picibanil resulted in acute and long-term neurophysiological changes, which were associated with diffuse white matter damage and subcortical neuronal loss. The neural injury was not affected by the dose of Picibanil. These findings provide valuable information for clinical studies testing antenatal Picibanil treatment for fetal hydrothorax.