Cerebral Palsy (CP) is a complex multifactorial disorder, affecting approximately 2.5-3 per 1000 live term births, and up to 22 per 1000 prematurely born babies. CP results from injury to the developing brain incurred before, during or after birth. The most common form of this condition, spastic CP, is primarily associated with injury to the cerebral cortex and sub-cortical white matter as well as the deep gray matter. The major etiological factors of spastic CP are hypoxia/ischemia, occurring during the last third of pregnancy and around the birth age. In addition, inflammation has been found to be an important factor contributing to brain injury, especially in term infants. Other factors, including genetics, are gaining importance. The classic Rice-Vannucci hypoxia-ischemia model (in which 7-day-old rat pups undergo unilateral ligation of the common carotid artery followed by exposure to 8% oxygen hypoxic air) is a model of neonatal stroke which has greatly contributed to cerebral palsy research. In this model brain damage resembles that observed in severe CP cases. This model, and its numerous adaptations, allows one to finely tune the injury parameters to mimic, and therefore study, many of the pathophysiological processes and conditions observed in human patients. Investigators can recreate the hypoxia/ischemia and inflammation, which cause brain damage and subsequent motor and cognitive deficits. This model further enables the examination of potential approaches to achieve neural repair and regeneration. In the present review, we compare and discuss the advantages, limitations, and the translational value for cerebral palsy research of hypoxia-ischemia models of perinatal brain injury.

J. Neurochem. (2012) 121, 607–618. Although neural c‐Jun is essential for successful peripheral nerve regeneration, the cellular basis of this effect and the impact of c‐Jun activation are incompletely understood. In the current study, we explored the effects of neuron‐selective c‐Jun deletion, substitution of serine 63 and 73 phosphoacceptor sites with non‐phosphorylatable alanine, and deletion of Jun N‐terminal kinases 1, 2 and 3 in mouse facial nerve regeneration. Removal of the floxed c‐jun gene in facial motoneurons using cre recombinase under control of a neuron‐specific synapsin promoter (junΔS) abolished basal and injury‐induced neuronal c‐Jun immunoreactivity, as well as most of the molecular responses following facial axotomy. Absence of neuronal Jun reduced the speed of axonal regeneration following crush, and prevented most cut axons from reconnecting to their target, significantly reducing functional recovery. Despite blocking cell death, this was associated with a large number of shrunken neurons. Finally, junΔS mutants also had diminished astrocyte and microglial activation and T‐cell influx, suggesting that these non‐neuronal responses depend on the release of Jun‐dependent signals from neighboring injured motoneurons. The effects of substituting serine 63 and 73 phosphoacceptor sites (junAA), or of global deletion of individual kinases responsible for N‐terminal c‐Jun phosphorylation were mild. junAA mutants showed decrease in neuronal cell size, a moderate reduction in post‐axotomy CD44 levels and slightly increased astrogliosis. Deletion of Jun N‐terminal kinase (JNK)1 or JNK3 showed delayed functional recovery; deletion of JNK3 also interfered with T‐cell influx, and reduced CD44 levels. Deletion of JNK2 had no effect. Thus, neuronal c‐Jun is needed in regeneration, but JNK phosphorylation of the N‐terminus mostly appears to not be required for its function.

In the current study, we explored the role of TNF cluster cytokines on the lipopolysaccharide (LPS)-mediated, synergistic increase in brain injury after hypoxic ischemic insult in postnatal day 7 mice. Pretreatment with moderate doses of LPS (0.3 μg/g) resulted in particularly pronounced synergistic injury within 12 h. Systemic application of LPS alone resulted in a strong upregulation of inflammation-associated cytokines TNFα, LTβ, interleukin (IL) 1β, IL6, chemokines, such as CXCL1, and adhesion molecules E-Selectin, P-Selectin and intercellular adhesion molecule-1 (ICAM1), as well as a trend toward increased LTα levels in day 7 mouse forebrain. In addition, it was also associated with strong activation of brain blood vessel endothelia and local microglial cells. Here, deletion of the entire TNF gene cluster, removing TNFα, LTβ and LTα completely abolished endotoxin-mediated increase in the volume of cerebral infarct. Interestingly, the same deletion also prevented endothelial and microglial activation following application of LPS alone, suggesting the involvement of these cell types in bringing about the LPS-mediated sensitization to neonatal brain injury.