Neuroprotective Strategies for the Neonatal Brain

Inserm, U676, Paris, France.
Anesthesia and analgesia (Impact Factor: 3.47). 07/2008; 106(6):1670-80. DOI: 10.1213/ane.0b013e3181733f6f
Source: PubMed


Injury to the perinatal brain is a leading cause of childhood mortality and lifelong disability. Cerebral palsy and cognitive impairment are usually related to periventricular white matter damage, which is seen chiefly in babies born before 32 wk gestational age, and to corticosubcortical lesions, which occur mainly in full-term infants. Despite recent improvements in neonatal care, no effective treatment for perinatal brain lesions is available. Several interventions, such as magnesium sulfate in preterm newborns and hypothermia in term newborns, are the focus of completed or continuing clinical trials. Improved understanding of the pathophysiological mechanisms involved in perinatal brain lesions helps to identify potential targets for neuroprotective interventions, as discussed in this review.

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Available from: Pierre Gressens, Apr 18, 2014
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    • "Current treatment options for the vulnerable neonate are very limited and development of new therapies remains a major challenge to medical science. HI cerebral injury is characterized by damaged or dying neurons , glia, and endothelial cells (Degos et al., 2008; Ferriero, 2004). The brain develops a restorative adaptive response to this injury consisting of early anti-inflammatory and anti-apoptotic signaling (Yang et al., 2007; Bartley et al., 2005; Hedtjarn et al., 2004; Allan and Rothwell, 2001). "
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    ABSTRACT: Mesenchymal stem cell (MSC) treatment is an effective strategy to reduce brain damage after neonatal hypoxia-ischemia (HI) in mice. We recently showed that a single injection with MSC at either 3 or 10 days after HI (MSC-3 or MSC-10) increases neurogenesis. In case of two injections (MSC-3+10), the second MSC application does not increase neurogenesis, but promotes corticospinal tract remodeling. Here we investigated GFP(+)-MSC engraftment level in the brain using quantitative-PCR analysis. We show for the first time that in the neonatal ischemic brain survival of transplanted MSC is very limited. At 3 days after injection ∼22% of transplanted MSC were still detectable and 18 days after the last administration barely ∼1%. These findings indicate that engraftment of MSC is not likely the underlying mechanism of the efficient regenerative process. Therefore, we tested the hypothesis that the effects of MSC-treatment on regenerative processes are related to specific changes in the gene expression of growth factors and cytokines in the damaged area of the brain using PCR-array analysis. We compared the effect of one (MSC-10) or two (MSC-3+10) injections of 10(5) MSC on gene expression in the brain. Our data show that MSC-10 induced expression of genes regulating proliferation/survival. In response to MSC-3+10-treatment a pattern functionally categorized as growth stimulating genes was increased. Collectively, our data indicate that specific regulation of the endogenous growth factor milieu rather than replacement of damaged tissue by exogenous MSC mediates regeneration of the damaged neonatal brain by MSC-treatment.
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    • "This leads to oedema formation and infiltration of inflammatory cells such as macrophages and neutrophils into the brain, but also to relocation and proliferation of resident microglia at the injured site (Alvarez-Diaz et al., 2007; Bona et al., 1999; Degos et al., 2008; Hudome et al., 1997; McRae et al., 1995). The inflammatory cells can produce several pro‐inflammatory mediators that increase the inflammation further, as well as neurotrophic substances that promote neuronal survival (Alvarez-Diaz et al., 2007; Bona et al., 1999; Degos et al., 2008; Hedtjarn et al., 2004). "
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