Systemic inflammation disrupts the developmental program of white matter

Favrais, Géraldine; Looij, Yohan van de; Fleiss, Bobbi; Ramanantsoa, Nélina; Bonnin, Philippe; Stoltenburg‐Didinger, Gisela; Lacaud, Adrien; Saliba, Élie; Dammann, Olaf; Gallego, Jorge; Sizonenko, Stéphane; Hagberg, Henrik; Lelièvre, Vincent; Gressèns, Pierre

doi:10.1002/ana.22489

Cited by 350 publications

(453 citation statements)

References 52 publications

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“…These results also provide evidence that IL-1 is either the initiator of the molecular cascades leading to brain damage, or has a central role in the regulation of these events, since the use of a specific antagonist confers protection for most of the parameters studied. This is in agreement with other reports, which showed the neurotoxic consequence of IL-1 (Cai et al, 2004;Crampton et al, 2011;Favrais et al, 2011;Girard et al, 2008;Green et al, 2012), and also with reports on the neuroprotective potential of IL-1Ra administration seen in experimental models of neonatal brain injury induced by pure HI in rodents at a later stage of development, equivalent to term human newborns (Hagberg et al, 1996;Martin et al, 1994). Thus, even if the mechanisms leading to brain damage are known to differ across developmental stages (Anthony et al, 1997;Brochu et al, 2011), IL-1Ra appears to exert its beneficial effects when administered in models of LPS and/or HI induced brain insults, occurring (at least for HI) either in the early preterm or term brain.…”

Section: Discussionsupporting

confidence: 94%

“…The beneficial effect of IL-1Ra administration could be even more important at this early developmental stage since recent work by Favrais et al showed that systemic administration of IL-1β at a specific early developmental stage (i.e. from P1 to P5) led to disrupted myelination and associated cognitive defects (Favrais et al, 2011). Since we observed that IL-1Ra was protective in LPS + HI but not in HI alone animals in some of the behavioral tests (i.e.…”

Section: Discussionmentioning

confidence: 99%

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Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries

Girard¹,

Sébire²,

Brochu³

et al. 2012

Brain, Behavior, and Immunity

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New therapeutic strategies are needed to protect neonates, especially premature newborns, against brain injury and associated neurobehavioral deficits. The role of pro-inflammatory cytokines, especially IL-1β, in the pathophysiological pathway leading to neonatal brain damage is increasingly recognized and represents an attractive therapeutic target. We investigated the therapeutic potential of postnatal systemic administration of the interleukin (IL)-1 receptor antagonist (IL-1Ra) in an animal model of perinatal brain injury using the insults most common to human neonates, i.e. prenatal exposure to inflammation and/or postnatal hypoxia-ischaemia (HI). We found that postnatal administration of IL-1Ra preserved motor function and exploratory behavior after either prenatal exposure to inflammatory agent lipopolysaccharide (LPS) or postnatal HI insult. The deleterious effect of combined prenatal LPS and postnatal HI on brain development was also alleviated by administration of IL-1Ra, as seen by the protected neural stem cell population, prevention of myelin loss in the internal capsule, decreased gliosis, and decreased neurobehavioral impairment. This study showed the distinct pattern of functional deficits induced by prenatal inflammation as compared to postnatal HI and the therapeutic potential of IL-1Ra administration against neonatal brain injury. Furthermore, our results highlight the potential for postnatal treatment of prenatal inflammatory stressors.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries

Girard¹,

Sébire²,

Brochu³

et al. 2012

Brain, Behavior, and Immunity

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“…Very preterm infants are exposed to multiple hypoxic and inflammatory events during and after birth. Systemic inflammation has been related to white matter injury and impaired development in both experimental and clinical studies (23)(24)(25). We have previously shown that perinatal inflammation is associated with a concomitant decrease in IGF-I concentrations in preterm infants (9).…”

Section: Discussionmentioning

confidence: 92%

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

et al. 2013

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“…Myelination deficits have also been reported in several other perinatal conditions, including moderate perinatal systemic inflammation (Favrais et al, 2011), perinatal hypoxic-ischemia (Huang et al, 2009), and white matter injury in the premature baby (Buser et al, 2012). Since it is known that neuronal-oligodendrocyte crosstalk is crucial for proper myelination (Lee and Fields, 2009), myelination impairment observed in the kernicterus mice may be attributable in part to a reduced number of viable axons limiting oligodendrocyte differentiation and myelination.…”

Section: Discussionmentioning

confidence: 98%

Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia

et al. 2015

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Bilirubin-induced neurologic dysfunction (BIND) and kernicterus has been used to describe moderate to severe neurologic dysfunction observed in children exposed to excessive levels of total serum bilirubin (TSB) during the neonatal period. Here we use a new mouse model that targets deletion of the Ugt1 locus and the Ugt1a1 gene in liver to promote hyperbilirubinemiainduced seizures and central nervous system toxicity. The accumulation of TSB in these mice leads to diffuse yellow coloration of brain tissue and a marked cerebellar hypoplasia that we characterize as kernicterus. Histologic studies of brain tissue demonstrate that the onset of severe neonatal hyperbilirubinemia, characterized by seizures, leads to alterations in myelination and glia reactivity. Kernicterus presents as axonopathy with myelination deficits at different brain regions, including pons, medulla oblongata, and cerebellum. The excessive accumulation of TSB in the early neonatal period (5 days after birth) promotes activation of the myelin basic protein (Mbp) gene with an accelerated loss of MBP that correlates with a lack of myelin sheath formation. These changes were accompanied by increased astroglial and microglial reactivity, possibly as a response to myelination injury. Interestingly, cerebellum was the area most affected, with greater myelination impairment and glia burden, and showing a marked loss of Purkinje cells and reduced arborization of the remaining ones. Thus, kernicterus in this model displays not only axonal damage but also myelination deficits and glial activation in different brain regions that are usually related to the neurologic sequelae observed after severe hyperbilirubinemia.

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Systemic inflammation disrupts the developmental program of white matter

Abstract: Moderate perinatal systemic inflammation alters the developmental program of the white matter. This insult induces a long-lasting myelination deficit accompanied by cognitive defects and MRI abnormalities, further supporting the clinical relevance of the present data.

Cited by 350 publications

References 52 publications

Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries

Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia

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