Hypoxia-ischemia (HI) during the perinatal period is a significant health problem for the newborn. The discovery of safe and effective therapies to combat perinatal HI remains an ongoing challenge for perinatal medicine. Understanding the interplay between numerous pathophysiological pathways that are activated by HI, might lead to more effective neuroprotective strategies to combat HI brain injury. In this thesis, we described novel therapeutic approaches to combat neonatal HI brain injury. Furthermore, we studied the contribution of several pathophysiological pathways involved in the development of HI brain damage. In the first part of this thesis, we studied the role of the transcription factor nuclear factor-kappa B (NF-kappaB) in HI brain damage in neonatal rats. NF-kappaB is a key transcription factor in regulating expression of many inflammatory and apoptotic targetgenes. We explored the potential therapeutic benefits of inhibiting NF-kappaB activity on HI brain damage. We show two distinct phases of NF-kappaB activity after HI; an early peak and a late-phase peak, which have opposite roles during brain injury. Inhibition of early NF-kappaB activity is neuroprotective and associated with inhibition of early pro-apoptotic events. Late NF-kappaB activity is indispensable for regulating anti-apoptosis. In contrast to the potent effects of NF-kappaB inhibition after HI on apoptosis, we could not detect any effect of NF-kappaB inhibition on cytokine expression. We unravelled that switching to the use of another transcription factor JNK/AP-1 is responsible for preserving cytokine production after HI. In the second part, we investigated the contribution of the free radical NO. to HI brain damage and explored whether the compound 2-iminobiotin (2-IB), a previously described inhibitor of nNOS and iNOS, is neuroprotective after HI in neonatal rats. Treating neonatal rats with 2-IB after HI did not have any effect on nitrate/nitrite, nitrotyrosine or iNOS expression in vivo or in vitro and we concluded therefore that 2-IB is not an inhibitor of iNOS and nNOS. Treatment with 2-IB after HI was neuroprotective only in female rats. We found evidence for gender dimorphism in the use of apoptotic pathways after HI; males show a proclivity for the use of caspase-independent apoptosis and females for the use of caspase-dependent apoptosis. In the third part of this thesis, we have explored the role of the kinase G protein-coupled receptor kinase 2 (GRK2) in neonatal HI brain damage. GKR2 has a well-described function in switching off signaling by G protein-coupled receptors (GPCR) and GRK2 can interact with several downstream signaling molecules like p38. In GRK2+/- mice, we observed an advanced onset and an exacerbation of gray and white matter damage compared to WT mice, which was not caused by an effect of low GRK2 on enhanced cerebral neutrophil infiltration. We investigated the contribution of low GRK2 in microglia to HI brain damage by a targeted deletion of microglial GRK2 using a CRE-Lox system. We demonstrate that neonatal mice with low microglial GRK2 show an advanced onset of HI brain damage. We conclude that enhanced p38 activation in microglia is involved in inducing the advanced onset of cerebral damage
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