Abstract
In Chapter 1 the possible mechanisms and the current promising neuroprotective strategies after neonatal hypoxia-ischemic (HI) brain injury have been summarized. Based on the mechanisms, therapies should be concentrated on inhibition of the production of reactive oxygen species or free radicals, anti-inflammation and anti-apoptosis in the early stage (first 6h
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after birth) while on stimulation of neurotrophic properties in a later stage. Combination of moderate hypothermia and pharmacological interventions is probably the next step of consideration. One important factor playing a role in brain injury is the hypoxia-inducible factor-1alpha (HIF-1alpha). During neonatal HI, HIF-1alpha protein expression is stabilized so that it can regulate the expression of several target genes, such as erythropoietin (EPO), which plays a role in neuronal cell survival and death. In Chapter 2, the role and regulation of HIF-1alpha in neonatal HI is summarized, and several possible pathways are described that are involved in promoting the neuroprotective effect of HIF-1alpha via inducing expression of the neurotrophic target genes while inhibiting its neurotoxic effects which increase the level of the pro-apoptotic protein p53. The neuroprotective properties of EPO have been reported, but contradicting evidence with respect to its efficacy exists. In Chapter 3, the effect of EPO treatment on short-and long-term outcome after HI was investigated in a p9 mice model. EPO showed to improve sensorimotor function and white matter damage, but did not reduce grey matter lesion volume. Furthermore, EPO also enhanced proliferation of progenitor cells in the brain. However, these modest neuroprotective effects were shown to be both dose-dependent and gender-dependent. In the present study, only female mice benefited from EPO after HI when treated with 5kU/kg (EPO). Moderate hypothermia is the only method available today for asphyxiated term newborns with moderate encephalopathy that has shown to have a modest neuroprotective effect provided the therapy is started within 6h after birth. Only 1 out of 9 children benefits from this intervention. In Chapter 4 and 5, the potential neuroprotective effects of 3h hypothermia was tested in a p7 rat HI model. With hypothermia alone (Chapter 4), the improvement of sensorimotor function and reduction in brain lesion were found only in females. We checked whether the combination of hypothermia and EPO improved the efficacy of the treatment instead of applying EPO alone in Chapter 5. However, no synergic or additive effect of the hypothermia-EPO combination was found in females. In males there was only a short-lasting improvement of sensorimotor function after the combined therapy of hypothermia and EPO in males, which disappeared after 3 weeks. Apoptosis is thought to play an important role in neonatal HI brain damage. Neuronal p53 acts as a transcription factor for various pro-apoptotic molecules. Moreover, it has a direct effect on mitochondria. In Chapter 6, pifithrin-mu, a p53 inhibitor, was administrated to the p7 rat after HI. Pifithrin-mu completely prevented the HI-induced transport of p53 to the mitochondria resulting in improved sensorimotor and cognitive function and in a profound reduction in brain lesion
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