Neuroprotection of the newborn brain: therapeutic targets & behavioral outcome

Abstract

The research described in this thesis focuses on the evaluation of neuroprotective strategies in animal models for neonatal HI. Neuroprotection was assessed by not only by histology but was focused on the behavioral outcome seen in animal models for neonatal HI. First the role of erythropoietin after hypoxic-ischemic (HI) brain injury was studied. An overview of the studies in which erythropoietin (EPO) has been used as a neuroprotective agent in in vitro and in vivo models for HI-injury is provided. Next the potential beneficial consequences of combining two individually neuroprotective compounds; EPO and DFO was explored. Furthermore, it is shown that severe but also mild cerebral injury could lead to distinct long-term motor impairments. Moreover it was demonstrated that the modified hole board was sensitive enough as a test to visualize impairments in cognition after severe and mild HI. Next the beneficial effects on histological and functional (motor- and cognitive) outcome of inhibition of the NF-?B pathway after neonatal HI was explored using a specific NEMO-binding domain peptide. The histological improvements of JNK-inhibition and the molecular basis that may underlie the neuroprotection afforded by the specific JNK-binding domain (JBD)-peptide were demonstrated. In addition we employed behavioral tests to show improved motor functions and cognition after JBD-treatment.